Biomedical subjects

D F Lewis

Publications and source records attributed to D F Lewis.

At least 127 records · Page 7Linked to original sources

PubMed1992

Molecular modelling and site-directed mutagenesis on a bovine anti-testosterone monoclonal antibody.

A three-dimensional (3D) molecular model of the antigen-combining site of a bovine anti-testosterone monoclonal antibody has been constructed. In the model, the CDRs, and a single heavy chain framework region residue (Trp47), associate to form a hydrophobic cavity large enough to accommodate a single molecule of testosterone. Tyr97 of CDR-H3 lies at the bottom of the cavity with its hydroxyl group exposed to solvent. Using the model and data from binding studies, we predicted that the cavity forms the antibody's paratope and on binding testosterone a hydrogen bond is formed between Tyr97 of CDR-H3 and the hydroxyl group on the D-ring of testosterone. This prediction has subsequently been tested by site-directed mutagenesis. An antibody with phenylalanine in place of tyrosine at position 97 in CDR-H3 has its affinity reduced by approximately 800 fold. The reduction in binding energy associated with the reduced affinity has been calculated to be 3.9 kcal/mol which is within the range (0.5-4.0 kcal/mol) expected for the loss of a single hydrogen bond. The model has been used to suggest ways of increasing the antibody's affinity for testosterone.

Amino Acid Sequence↗

PubMed1992

Effects of digital vaginal examinations on latency period in preterm premature rupture of membranes.

OBJECTIVE: To compare the clinical outcome in patients with preterm premature rupture of membranes (PROM) who had a sterile speculum examination with those having a digital vaginal examination. METHODS: We studied 271 singleton pregnancies complicated by preterm PROM from the Memorial Medical Center of Long Beach Perinatal Outreach program that met the criteria for expectant treatment from January 1986 to April 1990. Patients were not included in the study if they had multiple gestations, cerclage, advanced labor, or any indication for delivery on admission (eg, mature lung profile, chorioamnionitis). All subjects were maternal transports to our tertiary care facility and were managed similarly by our perinatal group. The women were questioned as to whether a digital vaginal examination had been performed before transport. Latency period and other obstetric characteristics were then compared. The latency period, defined as days from rupture of membranes until active intervention was initiated or labor began spontaneously, was also stratified by gestational age. RESULTS: One hundred twenty-seven subjects had a digital vaginal examination and 144 had a sterile speculum examination. A significantly (P less than .0001) shorter mean latency period (2.1 +/- 4.0 versus 11.3 +/- 13.4 days) was found in those who had a digital vaginal examination. In addition, a shorter latency period was noted for each gestational age. No difference in uterine activity or cervical dilatation and effacement was noted between the groups on admission. CONCLUSION: Digital vaginal examinations performed on patients whose pregnancies are complicated by preterm PROM appear to shorten significantly the latency period.

Chorioamnionitis↗

PubMed1992

Labor in the gravida with 10 or more years between pregnancies.

It has been suggested that women who have had a pregnancy interval of 10 or more years would have prolonged labor in pregnancies after the first, as do primigravidas. In a series of 94 multiparas with 10 or more years between pregnancies and 63 age-matched, multiparous controls, there was no significant difference in the length of the latent phase of labor or of the first, second and third stages of active labor in the two groups. The concept of a "physiologic primigravida" in these cases should be abandoned.

Adult↗

PubMed1991

In utero appearance of idiopathic infantile arterial calcification: ultrasound study of a 28-week fetus.

An ultrasound study of a 28-week gestation demonstrated changes of poor cardiac function associated with calcifications of the wall of major arteries. Sudden in utero deterioration into hydrops prompted the delivery of a female infant who was diagnosed at autopsy of having a rare disease entity, idiopathic infantile arterial calcification. When a hydropic fetus is defined by ultrasound, this rare diagnosis should be included in the diagnostic considerations. Recent reports suggest successful therapy regimens for an otherwise fatal disease, making accurate diagnosis especially important.

Journal Article↗

PubMed1991

Does amniotic fluid index affect the accuracy of estimated fetal weight in preterm premature rupture of membranes?

Estimated fetal weights play a critical role in the management scheme of patients with preterm premature rupture of membranes but are often technically difficult to obtain in these patients because of low amniotic fluid volume. Previous studies have had conflicting data as to the accuracy of estimated fetal weights in preterm premature rupture of membranes. This study was undertaken to evaluate the effect of amniotic fluid index on the accuracy of estimated fetal weights in pregnancies complicated by preterm premature rupture of membranes. Over a 2-year period at Long Beach Memorial Medical Center, 98 patients with preterm premature rupture of membranes who had an ultrasonographic examination with estimated fetal weights and amniotic fluid index performed within 48 hours of delivery were identified and compared with a control group of 55 patients in preterm labor with normal amniotic fluid index for gestational age, also obtained within 48 hours of delivery. Shepard and Hadlock formulas were used to estimate fetal weight. Results were measured in percent error from the actual birth weight. All birth weights were less than 2000 gm. No statistical differences were identified. The value of amniotic fluid index did not affect the accuracy of predicted estimated fetal weight in preterm premature rupture of membranes. Predicted estimated fetal weight of patients with preterm premature rupture of membranes appears to be as accurate as predicted estimated fetal weight in pregnancies with normal amniotic fluid volumes.

Amniotic Fluid↗

PubMed1991

Correlation of amniotic fluid index and nonstress test in patients with preterm premature rupture of membranes.

The amniotic fluid index and the nonstress test are commonly used in the expectant management of preterm premature rupture of membranes. This study was designed to investigate the interrelationship of the nonstress test and the amniotic fluid index during the preterm rupture of membranes latency period. Fifty patients with preterm premature rupture of membranes for greater than 48 hours were prospectively followed with daily 1-hour nonstress tests and blinded, daily amniotic fluid index examinations (totaling 422 evaluations). The overall average daily amniotic fluid index was statistically lower in the earlier gestations and nulliparous patients but was not influenced by the fetal position or nonlaboring uterine activity. An increased incidence of variable decelerations and nonreactive nonstress tests was associated with a significantly lower overall average daily amniotic fluid index, but these differences were beyond the standard precision of the amniotic fluid index examination. The daily nonstress test appears to identify clinically significant lower fluid volumes during the latency period and should remain the mainstay in the management of preterm premature rupture of membranes.

Adult↗

PubMed1991

Rate of recurrence of preterm premature rupture of membranes in consecutive pregnancies.

The reported incidence of preterm premature rupture of membranes ranges between 1% and 2% of all pregnancies. The rate of recurrence is poorly defined. The goal of this study was to establish the frequency of recurrence in a high-risk referral practice. Over a 5-year period we identified 121 patients with preterm premature rupture of membranes who had a minimum of two consecutive pregnancies under our care, resulting in a total of 255 pregnancies for analysis. Recurrent preterm premature rupture of membranes occurred in 39 of 121 patients, for a rate of 32.2% (95% confidence interval, 23.9 +/- 40.5). We were unable to demonstrate an association between the estimated gestational age at the time of rupture in the index pregnancy, latency period, interval between pregnancies, and the probability of repeat preterm premature rupture of membranes in the next pregnancy. We conclude that patients with preterm premature rupture of membranes should be counseled regarding the significant risk of recurrence and need to have close follow-up in their subsequent pregnancies.

Adult↗

PubMed1991

The 1990 Pharmaceutical Manufacturers Association of Canada keynote lecture. The role of the cytochromes P450 in the detoxication and activation of drugs and other chemicals.

The roles of the cytochromes P450 are reviewed, with emphasis on their involvement in the detoxication of drugs and chemicals, the activation of carcinogens, and the toxicity of drugs. Cytochromes P450 have different characteristics. P450I mostly activates carcinogens and other chemicals by forming oxygenated reactive intermediates, which are also associated with the formation of neoantigens and immunotoxicity. P450IIE has a propensity to form oxygen radicals, which are cytotoxic and carcinogenic; other cytochromes generate oxygen radicals by futile cycling when activated by difficulty metabolized substrates. Novel procedures for the safety evaluation of chemicals are described; COMPACT is based on the computer graphic determination of the spatial conformation and electronic structure of chemicals to enable their activating cytochromes P450, and hence their toxicity, to be established; ENACT is based on quantifying the induction of individual cytochromes P450, since the extent of induction of P450I, and possibly other activating cytochromes, is directly related to the carcinogenic potential of the chemical.

Animals↗

PubMed1990

A retrospective study of the molecular toxicology of benoxaprofen.

The molecular and electronic structural characteristics of the hepatotoxic and phototoxic anti-rheumatic drug, benoxaprofen, indicate that it falls in the interface between the area of parametric space associated with substrates of cytochrome P450I and that associated with substrates of other cytochromes P450, combining fairly planar molecular geometry (area/depth2 = 2.5) with relatively low activation energy (delta E = E(LEMO) - E(HOMO) = 12.0). Benoxaprofen may therefore be a substrate for cytochrome P450I so that, like many other P450I substrates, it may be oxygenated to a reactive intermediate, thereby causing hepatotoxicity. Benoxaprofen also has a molecular structure closely similar to that of clofibrate and may thus be a possible substrate for cytochrome P450IV and result in hepatic peroxisomal proliferation. The structural similarity of benoxaprofen with the furocoumarin, psoralen, is associated with its known phototoxicity. QSAR analysis of the acute toxicities and anti-inflammatory activities of 16 analogues of benoxaprofen has been undertaken to identify a drug candidate likely to have similar anti-inflammatory activity to benoxaprofen but with lower toxicity.

Liver↗

PubMed1990

Feprazone: an inducer of the P450 II B family of proteins in the rat.

The ability of feprazone to induce the hepatic microsomal mixed-function oxidases was investigated in the rat, with emphasis being placed on the nature of the cytochrome P-450 family induced. Treatment with feprazone enhanced the p-hydroxylation of aniline and the dealkylations of benzphetamine and pentoxyresorufin but had no effect on the O-deethylation of ethoxyresorufin. The same treatment had no major effect on total cytochrome P-450 levels but increased the spectral interaction of metyrapone with reduced cytochrome P-450. Immunoblots employing monospecific polyclonal antibodies revealed that feprazone induces the apoprotein levels of the P450 II B, but not of the P450 I, family. It is concluded that feprazone is an inducer of the rat hepatic mixed-function oxidase system showing selectivity toward the P450 II B family.

Animals↗

PubMed1990

Color flow Doppler--a useful instrument in the diagnosis of vasa previa.

Vasa previa is associated with an increased perinatal mortality rate and rarely is diagnosed in the antepartum period. We present a case in which vasa previa was correctly diagnosed by use of color flow Doppler imaging. This modality is a valuable adjunct in the evaluation of patients suspected to have vasa previa.

Blood Vessels↗

PubMed1990

Fetal gastroschisis and omphalocele: is cesarean section the best mode of delivery?

There has always been controversy regarding the mode of delivery of fetuses with abdominal wall defects. Prior studies may have been biased in this evaluation as a result of the effects of delay in repair, transport of the fetus to level III facilities, and antenatal diagnosis compared with an unsuspected diagnosis. The purpose of this study was to evaluate mode of delivery at level III institutions with access to complete care to determine if cesarean section improved outcome. One hundred eight infants were treated in the study period for abdominal wall defects. Fifty-six infants met all criteria for admission to the study. No difference in neonatal morbidity or mortality was identified. No difference was found in infants who were born by elective cesarean section compared with infants delivered after labor ensued. In conclusion, we found no evidence that cesarean section or avoidance of labor improved outcome in fetuses with uncomplicated abdominal wall defects.

Abdominal Muscles↗

PubMed1990

Mechanism of the in vitro antimutagenic action of retinol.

The antimutagenic action of retinoids against three amino-imidazoazaarene pre-carcinogens, i.e. 2-amino-3-methylimidazo(4,5-f)quinoline (IQ), 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (MeIQ) and 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx), was investigated using the Ames test and hepatic activation systems derived from rats pretreated with Aroclor 1254. Both retinol and retinal, when incorporated into the S9 activation system, gave rise to a concentration-dependent decrease in the mutagenicity of all three mutagens, retinol being generally the more effective. Retinol suppressed the mutagenic activity of IQ even when isolated microsomes were used as activation systems. Moreover, retinol gave rise to a concentration-dependent inhibition of the microsomal dealkylations of pentoxy- and benzyloxy- and, especially, ethoxy-resorufin, but had no effect on the NADPH-dependent reduction of cytochrome c. Exposure of the bacteria to retinol with subsequent removal of the vitamin did not influence the mutagenicity of IQ. It is concluded that retinoids suppress the mutagenicity of aminoimidazoazaarenes and this is achieved through inhibition of their cytochrome P450-dependent metabolic activation. Retinol is a non-selective in vitro inhibitor of the hepatic cytochrome P450-dependent mixed function oxidase system as predicted by a computer graphic analysis of its molecular shape.

Animals↗

PubMed1990

A prospective toxicity evaluation (COMPACT) on 40 chemicals currently being tested by the National Toxicology Program.

The computer-optimized molecular parametric analysis of chemical toxicity (COMPACT) procedure has been used to determine the molecular conformation and electronic structure of a series of 40 chemicals (out of a total of 44). The procedure can evaluate whether they interact with the active site of cytochrome P450 I or to the binding site of the Ah receptor, and hence to manifest carcinogenicity/toxicity. This is in response to the recent publication by Tennant et al. and their invitation to participate in a prospective identification of potential mutagenicity/carcinogenicity of these 44 chemicals. Correlation of COMPACT with potential genotoxicity was 25/40 (63%); COMPACT also predicted toxicity/carcinogenicity in 10 chemicals (25%) considered to be potentially non-genotoxic (naphthalene, promethazine, resorcinol, p-nitrophenol, tricresyl phosphate, bis(bromoethyl) propanediol, 3,4-dihydrocoumarin, theophylline, triamterene and chloramine), and predicted the absence of toxicity in four chemicals (10%) considered to be potentially genotoxic (methyl bromide, hydrazoic acid, 2,3-dibromo-1-propanol and 1,2,3-trichloropropane).

Binding Sites↗

PubMed1990

Antibiotic prophylactic uterine lavage in cesarean section: a double-blind comparison of saline, ticarcillin, and cefoxitin irrigation in indigent patients.

The purpose of this present study was to determine whether intraoperative antibiotic uterine irrigation was effective in reducing febrile morbidity (Part 1), and to determine whether ticarcillin disodium (Ticar) or cefoxitin sodium (Mefoxin) was the more effective solution (Part 2). The indications for cesarean section had an effect on febrile morbidity. In patients having nonelective cesarean section, febrile morbidity was high, occurring in 62.7% of the saline control group and 32.9% of those receiving ticarcillin disodium irrigation. In patients having elective cesarean section, febrile morbidity was lower (28% in the saline control group and 8.3% in the ticarcillin group [P less than or equal to .05]). Ticarcillin and cefoxitin were equal in reducing postoperative febrile morbidity. The use of prophylactic antibiotics, therefore, is indicated both in high-risk patients having nonelective cesarean section and in low-risk patients having elective repeat cesarean section.

Adult↗

PubMed1990

Studies on the cytochrome P-450 of avocado (Persea [corrected] americana) mesocarp microsomal fraction.

1. Because of the low concentration of cytochrome P-450 in avocado fruit, microsomal fractions were prepared using polyethylene glycol aggregation and low-speed centrifugation, thus avoiding the need for high-speed centrifugation of large volumes of post-mitochondrial supernatant. Recoveries of cytochrome P-450 by this means (0.29 nmol/g tissue) were similar to those after the usual high-speed centrifugation preparation (0.26 nmol/g). The cytochrome P-450 content of tulip bulb (0.30 nmol/g) was similar to that of avocado, but both plant tissues had much lower P-450 contents than did rat liver (13.0 nmol/g). 2. Spectral studies indicate that cytochrome P-450 of avocado mesocarp microsomal fraction binds fewer substrates than does the rat liver enzyme system. Type I binding spectra are given by fatty acids (C7-C14), aryl hydrocarbons (C7-C12), p-chloro-N-methylaniline and N,N-dimethylaniline. Type II binding is seen with inhibitors of mammalian cytochrome P-450 such as metyrapone, and with the imidazole antifungal agents such as clotrimazole. 3. These binding spectra provide a rapid method for identifying possible substrates and inhibitors of avocado cytochrome P-450, and also provide information concerning the nature of the active site of avocado cytochrome P-450. 4. Avocado cytochrome P-450 catalysed the N-demethylation of N,N-dimethylaniline (17.1 nmol/min per nmol P-450) and p-chloro-N-methylaniline (13.1 nmol/min per nmol P-450), and the hydroxylation of lauric (dodecanoic) acid (1.1 nmol/min per nmol P-450).

Aniline Compounds↗

PubMed1990

Current problems in the evaluation of chemical safety.

Current problems in the safety evaluation of chemicals, including species differences in chemical toxicity, the difficulty in predicting whether metabolism will result in detoxication or activation, the different metabolic roles of tissue cytochromes P-450, and the significance of oxygen radical formation, are reviewed. A number of specific chemical problems are discussed, including the safety evaluation of benzene, methylene dichloride, DDT, dieldrin, TCDD, the PCBs, and the hepatotoxic drugs: benoxaprofen and tienilic acid. Two novel methods for the prospective evaluation of chemical toxicity are described, namely (i) computer optimized parametric analysis for chemical toxicity (COMPACT) based on the computer graphic determination of chemical structure and its relationship to specific cytochromes P-450 and hence toxicity, and (ii) enzyme activation in chemical toxicity (ENACT) based on the induction of specific cytochromes P-450 by the chemical, from which toxicity can be predicted.

Animals↗

PubMed1990

Quantitative structure-activity relationships within a series of melatonin analogs and related indolealkylamines.

The results of molecular orbital calculations by the complete neglect of differential overlap, 2nd version on 10 indolealkylamines and amides related to melatonin are reported. Quantitative structure-activity relationships have been derived by regression analysis of electronic structural parameters and biological data in the form of melatonin receptor affinities. On the basis of these results, together with electrostatic potential energy calculations, a possible receptor binding site model is proposed.

Binding Sites↗