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Biomedical subjects

S K Sharma

Publications and source records attributed to S K Sharma.

At least 289 records · Page 16Linked to original sources
PubMed1995

Simultaneous mutations at Tyr-181 and Tyr-188 in HIV-1 reverse transcriptase prevents inhibition of RNA-dependent DNA polymerase activity by the bisheteroarylpiperazine (BHAP) U-90152s.

The replacement of either Tyr-181 or Tyr-188 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) by the corresponding HIV-2 RT amino acids Ile-181 or Leu-188 is known to result in active mutant enzymes (Y181I; Y188L) with virtual loss of sensitivity towards three structural classes of nonnucleoside RT inhibitors; L-697,661, nevirapine, and TIBO R82913. The bisheteroarylpiperazine (BHAP) U-90152S, a highly specific inhibitor (IC50, 0.29 +/- 0.01 microM) of HIV-1 RT, inhibited the recombinant Y181I and Y188L HIV-1 RT mutants with IC50 values of 3.6 +/- 0.15 microM and 0.71 +/- 0.02 microM, respectively. Construction and in vitro analysis of double mutants Y181I/Y188L and Y181C/Y188L of HIV-1 RT showed > 150-fold resistance to U-90152S. An HIV-2 RT mutant containing amino acids 176-190 from HIV-1 RT acquired full sensitivity to U-90152S (IC50, 0.26 +/- 0.01 microM). It is concluded that simultaneous mutations at Tyr-181 and Tyr-188 of HIV-1 RT promotes resistance to U-90152S.

Amino Acid Sequence↗
PubMed1995

Mechanism of resistance to U-90152S and sensitization to L-697,661 by a proline to leucine change at residue 236 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase.

Bisheteroarylpiperazines (BHAPs) are highly specific inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). BHAP-resistant HIV-1 is sensitized to other classes of nonnucleoside RT inhibitors and this has been primarily attributed to a proline-to-leucine substitution at amino acid 236 (P236L) of HIV-1 RT. To understand the basis for the in vitro sensitization-resistance phenomenon, single base pair mutations at amino acid P236 in HIV-1 RT were introduced to obtain P236L, P236T, P236H, P236R, and P236A HIV-1 RT mutants. Active HIV-1 RT mutants H235W, D237T, and H235W/D237T/T240K, containing substitutions from HIV-2 RT, were also cloned, expressed, and purified. Three BHAPs (U-88204E, U-87201E, and U-90125S) and the pyridinone L-697,661 were selected to quantitatively assess the effects of these amino acid substitutions on sensitization to L-697,661 and resistance to the BHAPs. The HIV-1 RT mutants bearing single (H235W; D237T) or multiple (H235W/D237T/T240K) HIV-2 RT substitutions around the conserved P236 conferred little resistance or sensitization to these RT inhibitors. The inhibition profiles of the P236 HIV-1 RT mutants demonstrated a direct correlation between sensitization to L-697,661 and resistance to the BHAPs. These results suggest alterations in the shape of the binding pocket as the mechanism by which the P236L mutation confers resistance to the BHAPs and sensitization to L-697,661.

Amino Acid Sequence↗
PubMed1995

Altered glycine transport by cerebral tissue and decreased Na+ and Ca++ pump activities during organophosphorus-ester-induced delayed neurotoxicity development period.

Uptake of [U-14C] glycine during the organophosphorus-ester-induced delayed neurotoxicity (OPIDN) development period was studied. Diisopropyl fluorophosphate (DFP), a delayed neurotoxic organophosphorus ester was administered to adult rats and hens. Results showed a decreased accumulation of glycine in hen cerebral cortex slices during the delayed neurotoxicity development period. An altered sensitivity toward transport inhibitors 2,4-dinitrophenol and ouabain was observed in DFP-treated hens. An altered neuronal membrane function during the OPIDN development period is reported in the present work. Brain Na+, K(+)-ATPase and Ca(++)-ATPase activities decreased during the neurotoxicity development period. The decrease in Ca(++)-ATPase activity persisted in hens until the complete development of neurotoxic symptoms. Decreased Ca++ pump activity is correlated with altered membrane function during OPIDN.

2,4-Dinitrophenol↗
PubMed1995

Stability of the arterial to end-tidal carbon dioxide difference during anaesthesia for prolonged neurosurgical procedures.

This study was undertaken to examine the variation of the arterial to end-tidal PCO2 (Pa-PETCO2) difference during prolonged neurosurgical anaesthesia. Hyperventilation is often used to reduce intracranial pressure in neurosurgical patients. Continuous end-tidal CO2 monitoring is used as a guide between arterial CO2 measurements. We examined the stability of the Pa-PETCO2 difference in 21 patients undergoing elective craniotomies lasting greater than four hours. A balanced neuroanaesthetic technique was used with the ventilation variables at the discretion of the attending anaesthetist. Once patients were positioned for surgery, simultaneous samples of arterial PCO2 through an arterial catheter, and end-tidal PCO2 via a mass spectrometer were obtained. The Pa-PETCO2 differences of each patient were plotted against time and a slope was derived with simple linear regression. The mean slope for all patients was then computed. There were no changes in the Pa-PETCO2 difference with time (P > 0.05) suggesting a constant relationship between the arterial and end-tidal PCO2 measurements over time. We conclude that end-tidal PCO2 can be used as a reliable guide to estimate arterial PCO2 during neurosurgical procedures of greater than four hours duration once the Pa-PETCO2 difference has been established.

Adult↗
PubMed1995

Comparison of 26-gauge Atraucan and 25-gauge Whitacre needles: insertion characteristics and complications.

Ninety-six women undergoing post-partum tubal ligation under spinal anaesthesia were studied to compare 26G Atraucan with 25G Whitacre spinal needles for ease of insertion, number of attempts at needle insertion, cerebrospinal fluid (CSF) flow characteristics through the needles, quality of subsequent analgesia, and incidence of perioperative complications. A higher rate of successful dural puncture at the first attempt (40/50 vs 27/46, P < 0.05) and faster (mean +/- SD, 11.5 +/- 2.2 vs 13.5 +/- 2.4, P < 0.001) CSF flow through the needle was achieved with the Atraucan than with the Whitacre needle. The incidence of failed spinal (4% vs 5%) and post-dural puncture headache (PDPH) (4% vs 4.3%) was similar with both needles, but more patients experienced paraesthesiae during needle insertion with the Whitacre than with the Atraucan needle (15% vs 2%, P < 0.05). We conclude that the use of the 26G Atraucan needle is associated with a higher rate of successful identification of the subarachnoid space at the first attempt, faster CSF backflow, and fewer paraesthesia when compared with the 25G Whitacre needle.

Adult↗
PubMed1995

Randomized trial of epidural versus intravenous analgesia during labor.

OBJECTIVE: To compare the effects of epidural analgesia with intravenous (IV) analgesia on the outcome of labor. METHODS: Thirteen hundred thirty women with uncomplicated term pregnancies and in spontaneous labor were randomized to be offered epidural bupivacaine-fentanyl or IV meperidine analgesia during labor. RESULTS: Comparison of the allocation groups by intent to treat revealed a significant association between epidural allocation and operative delivery for dystocia. However, only 65% of each randomization group accepted the allocated treatment. Four hundred thirty-seven women accepted and received meperidine as allocated, and they were compared with 432 women accepting epidural allocation. Significant associations resulted between epidural administration and prolongation of labor, increased rate of oxytocin administration, chorioamnionitis, low forceps, and cesarean delivery. Because of the high rate of noncompliance with treatment allocation, a multifactorial regression analysis was performed on the entire cohort, and a twofold relative risk of cesarean delivery persisted in association with epidural treatment. The impact of epidural treatment on cesarean delivery was significant for both nulliparous and parous women (risk ratios 2.55 and 3.81, respectively). Epidural analgesia provided significantly better pain relief in labor than did parenteral meperidine. CONCLUSION: Although labor epidural analgesia is superior to meperidine for pain relief, labor is prolonged, uterine infection is increased, and the number of operative deliveries are increased. A two- to fourfold increased risk of cesarean delivery is associated with epidural treatment in both nulliparous and parous women.

Adult↗
PubMed1995

Monoclonal antibody against human glioblastoma multiforme (U-87MG) immunoprecipitates a protein of molecular mass 38 kDa and inhibits tumor growth in nude mice.

A monoclonal antibody 6DS1 against a human glioblastoma multiforme cell line U-87MG recognizes a tumor-specific, cell surface antigen of human glioblastoma cell lines. Partial cross-reactivity is observed with two human neuroblastoma cell lines, SK-N-SH and SK-N-MC, with little or no reactivity towards a rat glioma cell line C6 or normal human adult and fetal brain tissues. The antibody recognizes an antigen of molecular mass 38 kDa as inferred from Western blot analysis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the immunoprecipitate. The monoclonal antibody 6DS1 inhibits both the attachment to substratum and growth of U-87MG cells. It strongly cross-reacts with xenotransplants of U-87MG cells and inhibits tumorigenesis (subcutaneous implants of U-87MG cells) in nude mice.

Animals↗
PubMed1995

Angioplasty of complex lesions in ischemic rest angina: results of the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) trial.

OBJECTIVES: This study sought to analyze the role of complex lesion morphology on the acute results of angioplasty. BACKGROUND: Acute complications of angioplasty are higher in unstable than in stable angina. The unstable culprit lesion is usually complex, indicative of plaque disruption and thrombus formation. Previous nonrandomized studies have shown that the presence of intracoronary thombus increases morbidity after coronary angioplasty. The role of complex morphology in coronary angioplasty outcome was studied in a prespecified subgroup analysis of a large multicenter coronary angioplasty trial. METHODS: The results of coronary angioplasty from the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) trial were analyzed. This large trial randomized 469 patients in double-blinded manner to receive either intracoronary urokinase or placebo during coronary angioplasty of the culprit lesion in ischemic rest angina with or without recent infarction. The study presented here analyzes in detail the results of coronary angioplasty in complex versus simple lesions in the urokinase and placebo groups. Complex lesions were defined before angioplasty by a core laboratory as having one or more of the following: irregular borders, overhanging edges, ulcerations or intraluminal filling defects proximal or distal to the lesion. RESULTS: Of the 469 patients, 458 had identifiable culprit lesions, of which 245 were complex and 213 were simple. Complex lesions were associated with a higher abrupt closure rate than simple lesions (10.6% vs. 3.3%, respectively, p < 0.003). Patients with complex lesions also had higher recurrent in-hospital angina (p < 0.02) and emergent bypass surgery (p < 0.02). Further analysis of complex lesions revealed that abrupt closure was particularly high in the urokinase group (15.0% vs 5.9% for the placebo group, p < 0.03), and most abrupt closures were thrombotic. Composite clinical end points were also significantly higher with complex lesions and urokinase. In the placebo group, complex lesions had a higher abrupt closure rate as well as postcoronary angioplasty filling defects, but clinical end points were not significantly different. CONCLUSIONS: Complex lesions before coronary angioplasty increase acute complication rates after coronary angioplasty. Urokinase as administered in the TAUSA trial had significant adverse effects, especially in complex lesions. However, even in the placebo arm, complex lesions were associated with higher complication rates than simple lesions. Newer antithrombotic measures that particularly target the platelet may eventually decrease complication rates in these lesions.

Angina, Unstable↗
PubMed1995

Chronic lung inflammation in victims of toxic gas leak at Bhopal.

Bronchoalveolar lavage (BAL) studies in 20 patients at Bhopal, 1.3 +/- 0.4 yr and 2.7 +/- 0.6 yr after toxic gas exposure had revealed that the lower respiratory tract inflammation had progressed from initial macrophage alveolitis to macrophage-neutrophilic alveolitis. The interval between the two lavages was 1.4 +/- 0.6 yr. BAL studies in a new group of 24 patients 5.1 +/- 1.0 yr after exposure had confirmed chronic inflammation of the lower respiratory tract as evidenced by macrophage-neutrophilic alveolitis in these subjects as well. Clinical, radiographic and pulmonary function abnormalities were persistent in a proportion of subjects in both groups. Fibronectin (FN) levels were estimated in BAL fluid in 41 patients. Elevated FN levels were seen in 12 (29.3%) subjects and nine of these 12 had radiographic abnormalities. Severely exposed subjects (n = 30) had significantly higher BAL fibronectin levels compared to normal subjects and mild/moderately exposed subjects. Repeat FN estimations in BAL samples from 10 patients had revealed that five had abnormally high FN including three who had high FN on both occasions. The number of patients showing abnormal decline in pulmonary function was higher in patients with elevated FN than in patients with normal FN. Thus, persisting clinical, roentgenographic and ventilatory abnormalities, as well as macrophage-neutrophilic alveolitis along with abnormally elevated FN levels in a proportion of subjects, suggest the possibility that lung fibrosis can occur in subjects exposed to toxic gas at Bhopal.

Accidents, Occupational↗
PubMed1995

Anti-tumour effects of an antibody-carboxypeptidase G2 conjugate in combination with phenol mustard prodrugs.

ADEPT is an antibody-based targeting strategy for the treatment of cancer. We have developed two new prodrugs, 4-[N,N-bis(2-chloroethyl)amino]-phenoxycarbonyl-L- glutamic acid (PGP) and (S)-2-[N-[4-[N,N-bis(2-chloroethyl)amino]- phenoxycarbonyl]amino]-4-(5-tetrazoyl)butyric acid (PTP), which are cleaved by the bacterial enzyme CPG2 to release the 4-[N,N-bis(2-chloroethyl)amino] phenol drug. In vitro, both prodrugs are approximately 100- to 200-fold less potent than the parent drug (1 h IC50 = 1.4 microM) in LoVo colorectal tumour cells. These prodrugs have been evaluated for utility in ADEPT when used in combination with a conjugate of CPG2 and the F(ab')2 fragment of the anti-CEA monoclonal antibody, A5B7. The conjugate was shown to localise specifically to established LoVo tumour xenografts growing in nude mice and optimal tumour-normal tissue ratios were achieved after 72 h. Administration of either prodrug, at doses which cause 6-8% body weight loss, 72 h after administration of the A5B7-CPG2 conjugate to the LoVo tumour-bearing mice resulted in tumour regressions and growth delays of 14-28 days. The PTP prodrug in combination with a high dose of conjugate (10 mg kg-1) gave the best anti-tumour activity despite being a 10-fold worse substrate for CPG2 than PGP. Prodrug alone, active drug alone or prodrug in combination with a non-specific conjugate had minimal anti-tumour activity in this tumour model.

Aniline Mustard↗
PubMed1995

Plasma clearance of an antibody--enzyme conjugate in ADEPT by monoclonal anti-enzyme: its effect on prodrug activation in vivo.

The effect of anti-enzyme antibody clearance on prodrug turnover in antibody-directed enzyme prodrug therapy (ADEPT) has been studied. Mice bearing LS174T xenografts were given localising carboxypeptidase G2 (CPG)2 conjugate (AEC) and 19 h later galactosylated anti-CPG2 antibody (SB43-GAL). In regimen I prodrug was injected 5 h after SB43-GAL as previously described. In regimen 2 and 3 a shortened and extended clearance time was used in which prodrug was administered 0.5 h or 53 h after SB43-GAL respectively. Regimen 1 resulted in similar tumour and normal tissue levels of active drug to those of the control in which prodrug was given 72 h after AEC. SB43-GAL therefore accelerated clearance of enzyme allowing early administration of prodrug. In regimen 2, very high active drug levels were found in the liver, showing removal of AEC from the blood followed by reactivation of enzyme and extensive and rapid prodrug turnover. Active drug levels in tumour and blood reached similar peak levels to those of the control. Regimen 3 resulted in lower active drug levels in tissues, consistent with degradation and excretion of enzyme. Regimen 3 also produced the best tumour to normal ratios for active drug. Residual prodrug in tumour was unaffected by SB43-GAL, showing the advantage of galactosylation in minimising inactivation of CPG2 in tumour. By contrast, residual prodrug in blood persisted for longer when SB43-GAL was used. Circulatory clearance of enzyme with SB43-GAL allows prodrug to be administered expediently with reduced toxicity and with the prospect of increasing the dosage.

Adenocarcinoma↗
PubMed1995

Use of sevoflurane during elective cesarean birth: a comparison with isoflurane and spinal anesthesia.

This randomized study compared sevoflurane 1% and isoflurane 0.5% in terms of maternal and neonatal outcomes. In addition, neonatal outcome in both groups was compared with a cohort of patients delivered by cesarean birth using spinal anesthesia. Fifty-five patients presenting for elective cesarean birth under general anesthesia were randomly assigned to receive either sevoflurane 1% or isoflurane 0.5% in a 50% nitrous oxide and oxygen mixture for maintenance. Twenty patients requesting regional anesthesia received a subarachnoid block using 1.5 mL bupivacaine 0.75% in 8.25% dextrose with fentanyl 10 micrograms. Intraoperative hemodynamic variables and perioperative adverse events were recorded. Neonatal data included Apgar scores at 1 and 5 min, umbilical artery gas analysis, neurologic adaptive capacity scores (NACS) at 2 and 24 h, and a modified neonatal behavioral assessment scale (NBAS) at 24 h. Sevoflurane and isoflurane at equianesthetic concentrations (0.46 MAC-h [minimum alveolar anesthetic concentration hours]) were associated with similar blood pressure and heart rate changes during the operation. Blood loss, uterine tone, and perioperative complications were not problematic and were similar with the two drugs. No differences were seen in emergence times or in the time to being judged fit for discharge from the recovery room. Similarly, the level of postoperative comfort was the same in both groups. Comparing the general and the spinal anesthetic groups, no differences could be detected in neonatal outcome. Fluoride concentrations were modestly increased above preoperative levels in maternal and umbilical blood samples after sevoflurane administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

A survey of obstetric patients who refuse regional anaesthesia.

One hundred obstetric patients presenting for elective surgery who had refused regional anaesthesia were interviewed just prior to entering the operating room. In each case, the reason for refusing a regional technique was recorded. The most frequent reasons given were fear of backache (33%) and fear of the needle (28%). Anaesthetists should be aware of patients' concerns and be able to discuss the relevant issues.

Adolescent↗