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PubMed1992

[Cytochrome P-450: structure, function, induction and practical significance].

The liver contains a series of microsomal hemoproteins, called cytochromes P-450 which are mixed-function oxygenases involved in the metabolic oxygenation of diverse xenobiotic chemicals (drugs, pesticides, etc.). This enzyme system converts lipophilic foreign compounds into more water soluble products, thereby facilitating their elimination from the body. In general, cytochrome P-450-catalyzed oxidation results in detoxification, however the cytochromes P-450 can also convert certain xenobiotics to more toxic or carcinogenic products. Many of the individual isoenzyme forms of cytochrome P-450 are inducible by a wide variety of chemicals. After induction the concentration of total cytochrome P-450 in liver microsomes and the activity of different cytochrome P-450 forms increase. Elevated levels of cytochrome P-450 are the result of multiple mechanisms. Increased transcription of P-450 genes is a major mechanism of cytochrome P-450 induction. Higher levels of specific mRNAs are detectable soon after treatment with either "phenobarbital-like" or polycyclic aromatic compounds. Although increased transcription plays some role in the induction of cytochromes P-450 by other inducers like pregnenolone-16 alpha-carbonitrile (PCN)/glucocorticoids and "ethanol-type" compounds, post-transcriptional events are also very important. Cytochrome P-450 induction can be achieved by message stabilization and enhanced transport of mRNA from the nucleus to the cytoplasm that also increase the specific mRNA levels at the site of protein synthesis. Elevated cytochrome P-450 levels may also result from protein stabilization. Stabilization of cytochrome P-450 protein and/or mRNA are the main processes of induction by PCN/glucocorticoids and ethanol-type inducers. Although these mechanisms exist, they do not seem to be important in the induction by "phenobarbital-like" and "3-methylcholanthrene-like" inducers. The fact that induction is produced by a large variety of xenobiotics and is mediated by multiple mechanisms suggests that cytochrome P-450 system can provide increased protection for organisms in potentially hostile chemical environment. Since cytochrome P-450 induction is a characteristic response to chemicals for various living organisms ranging from microorganisms to man, it seems to be an adaptive mechanism for organisms to increase the chance for survival.

Cytochrome P-450 Enzyme System↗
PubMed1991

Neural induction.

The study of neural induction in Xenopus can be approached from two broad perspectives. One can study the competence of the ectoderm to respond to neural induction signals and any potential prepattern within the ectoderm. The second area of study involves the neural induction signals, in terms of the chemical nature of the signals, their sources, and their method of delivery. The neural competence of ectoderm has been studied by either grafting the ectoderm into areas which normally form neural tissue or by grafting tissues which normally induce neural structures onto the ectoderm to be tested. In general, it appears that ectoderm loses neural competence by midgastrula. However, there is some experimental evidence from various amphibian studies that the loss of neural competence in ectoderm does not occur simultaneously throughout all regions. It is not yet known if this phenomenon is also true in Xenopus. There appear to be several signaling events involved in the process of neural induction. Molecular probes have made it possible to study early steps in the neural induction and patterning processes which were not possible to study using only the development of neural morphology as a marker for neural induction. Antibodies directed against early epidermal versus neural epithelium indicate that the dorsal animal blastomeres are biased toward a neural pathway during early cleavage. Another signaling event occurs at early gastrula and the resulting dorsal ectoderm now responds more readily to some neural induction events than does the ventral ectoderm. The source of the early gastrula signals has been studied by a variety of methods, including exogastrula embryos, Keller sandwiches, and grafting a blastopore lip to the edge of competent ectoderm. The blastopore lip can send signals through the plane of the ectoderm capable of inducing competent ectoderm to become neural tissue. There are several issues relative to the process of neural induction which are not yet resolved. The major issue involves the mechanism of establishing pattern within the neural plate. Ectoderm appears to lose neural competence prior to the time when involuted dorsal mesoderm comes to underlie the anterior neural plate region. Several investigators have shown that information for expression of spatially restricted neural-specific molecules can travel through the ectoderm, independent of underlying dorsal mesoderm.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Differentiated induction of cytochrome P450b/e and P450p mRNAs by dose of phenobarbital in primary cultures of adult rat hepatocytes.

Phenobarbital induces cytochromes P450 (P450s) of not only the class IIB gene subfamily (i.e., P450b and P450e) but also the class IIIA gene subfamily (P450p and P450pcn2). To determine whether coinduction of these structurally dissimilar gene products involves the same mechanism, we examined the dose dependency of phenobarbital induction of the mRNAs for these four P450s in a new responsive system for primary monolayer cultures of adult rat hepatocytes on Matrigel, a reconstituted basement membrane. Two-day treatments of the cultures with phenobarbital produced marked dose-dependent increases in the levels of P450b, P450e, and P450p mRNAs, which reached maximal inductions ranging from 11- to greater than 193-fold. Although the dose-response relationships for the inductions of P450b and P450e mRNAs by phenobarbital were similar (ED50 = 1.5 x 10(-5) and 5.7 x 10(-6) M, respectively), the dose-response curve for the induction of P450p mRNA was positioned distinctly to the right (ED50 = 3.0 x 10(-4) M). This difference reflects a potency ratio of 20-fold for P450p/P450b mRNA induction. Phenobarbital also produced a weak dose-dependent induction of P450pcn2 mRNA, with a potency (ED50 = 3.4 x 10(-5) M) intermediate between those for P450b/e and P450p. In a similar experiment using two phenobarbital-like inducers, (trans)nonachlor and clotrimazole, the relative inductions of P450b, P450e, P450p, and P450pcn2 mRNAs proved to be similar to those produced by phenobarbital (P450p/P450b potency ratios = 14- and 16-fold, respectively). These findings provide strong further evidence in support of the newly emerging concept that "phenobarbital" induction of the responsive class IIB and class IIIA P450 isozymes likely reflects multiple mechanisms.

Animals↗
PubMed1983

Reciprocal effects of epidermal growth factor on key lipogenic enzymes in primary cultures of adult rat hepatocytes. Induction of glucose-6-phosphate dehydrogenase and suppression of malic enzyme and lipogenesis.

In primary cultured hepatocytes of adult rats epidermal growth factor (EGF) caused 2- to 3-fold induction of glucose-6-phosphate dehydrogenase (EC 1.1.1.49, G6P dehydrogenase) within 2 days. The effect of EGF was additive with a similar effect of insulin. The half-maximum dose of EGF for the induction was 1 ng/ml. Induction of this enzyme by these hormones was shown by immunotitration to be due to increase of the amount of enzyme. Furthermore, this increase in the amount of enzyme was found to result from increase of syntheses of mRNA and enzyme protein. In contrast, the induction of malic enzyme (EC 1.1.1.40, L-malate:NADP+) oxidoreductase) by insulin plus triiodothyronine was strongly suppressed by the concomitant addition of EGF. Induction of G6P dehydrogenase by EGF, like that by insulin, was not suppressed by either glucagon or dibutyryl cAMP, whereas that of malic enzyme was suppressed additively by EGF and dibutyryl cAMP. EGF also suppressed stimulation of lipogenesis by insulin, measured as incorporation of [1-14C]acetate into triglycerides and phospholipids. Another difference between the inductions of G6P dehydrogenase and malic enzyme was in their dependence on cell density; G6P dehydrogenase induction by insulin and EGF was high at low cell density (3 X 10(4) cells/cm2) and less at higher cell density (13 X 10(4) cells/cm2), whereas induction of malic enzyme was high at higher cell density and less at lower cell density. These results are consistent with the dual role of G6P dehydrogenase in lipogenesis in resting cells and in synthesis of nucleic acid in growing cells. Malic enzyme plays a role only for lipogenesis in mature hepatocytes.

Animals↗
PubMed1984

Epithelial induction of osteogenesis in embryonic chick mandibular mesenchyme studied by transfilter tissue recombinations.

The initiation of osteogenesis in the mandibular mesenchyme of the embryonic chick at 7 days is dependent upon an epithelial induction which occurs in the mandible up to the fourth day in ovo. In the present study, transfilter tissue recombinations were used to study this inductive mechanism. The epithelial and mesenchymal components of the mandibles were separated before the completion of the induction and recombined to form transfilter explants which were either cultured for 9 days or grafted onto the chorioallantoic membrane for host embryos for 7 days. Control experiments demonstrated that the tissue separation and recombination techniques did not interfere with the normal epithelial induction, and confirmed that mandibular mesenchyme isolated at this stage was incapable of forming bone. Bone was observed in 86% of the CAM-grafted intact mandible controls and in 80% of the cultured intact mandible controls. Bone failed to form in the mesenchyme of transfilter explants when Millipore filters with 0.45 micrometer pores were used. Bone was observed as frequently as in control explants when the mandibular mesenchyme was separated from its epithelium by 0.8 micrometer or 0.4 micrometer porosity Nuclepore filters. Only about 30% of the transfilter explants prepared with 0.1 micrometer porosity Nuclepore filters formed bone and none of the explants prepared with 0.03 micrometer porosity Nuclepore filters formed bone. SEM studies demonstrated a distinct correlation between the formation of bone in transfilter explants and the ability of the epithelium and mesenchyme to penetrate the pores of the filters. Thus, the present study provides evidence that the site of the induction is restricted to the epithelial-mesenchymal interface, and that the induction is not mediated by a diffusible substance. The nature of the inductive mechanism is discussed with respect to this and other recent studies which suggest that the induction may be mediated by a non-diffusible epithelial cell product resident in the epithelial basal lamina.

Animals↗
PubMed1982

Neural induction and the structure of the target cell surface.

Lectins (SBA and PSA) were used to provoke crowding and structural modifications of the presumptive ectoderm cell surface in order to investigate the role of the membrane organization of the competent target cells in neural induction. Are specific characteristics of the cell surface essential for this phenomenon to occur? From amphibian gastrulae, it is possible to obtain neural induction in vitro by association of presumptive ectoderm (target cells) with chordamesoderm (inductor tissue): 4 h of contact is sufficient in Pleurodeles waltl for transmission of the inductive signal. Very quickly, the treatment of the normal ectoderm by lectins (SBA-FITC or PSA-FITC) provoked surface modifications. Lectin-treatment (50 microgram ml-1, 30 min) of presumptive ectoderm did not result in any neural induction. Lectin-treatment (50 microgram ml-1, 30 min) of presumptive ectoderm previous to its association with the natural inductor for 4 h, disturbed the phenomenon: no induction. Similar treatment followed by association with the inductor for 24 h: induction. Treatment of SBA or PSA with their respective hapten inhibitors prior to addition to ectodermal cells completely blocked the suppressive effects on induction. The structural integrity of the membrane of competent target cells is necessary for neural induction to occur. The cell membrane could thus play, directly or indirectly, an active role in the specificity of this process.

Animals↗
PubMed1998

Induction with levomethadyl acetate: safety and efficacy.

BACKGROUND: Levomethadyl acetate hydrochloride (known as LAAM) is a mu-opioid agonist approved for the treatment of opioid dependence. Clinical trials comparing LAAM and methadone have reported lower patient retention rates during LAAM induction; however, this may reflect dose and schedule differences. Few studies have systematically examined LAAM dose induction. This study compared induction with 3 different LAAM dosage levels. METHODS: In a randomized, double-blind trial, male and female opioid-dependent patients (N = 180) were assigned to 1 of 3 LAAM doses. The low-dose (25 mg) induction was constant from the onset of treatment, the medium-dose (50 mg) induction lasted 7 days, and the high-dose (100 mg) induction lasted 17 days. Safety and efficacy were assessed on retention, urinalysis and self-reported drug use, symptoms, and patient ratings of medication adequacy. RESULTS: The high-dose group had significantly fewer illicit opioid-positive urine samples in weeks 3 and 4 as compared with the low-dose group. The high-dose group had significantly lower self-reported heroin craving in weeks 2 and 3. All groups demonstrated significant decreases in illicit drug use, withdrawal symptoms, and depression. There were no between-group differences in retention; however, there was a trend (P = .08) for lower retention and a greater number of agonist adverse effects were observed in the high-dose group. Overall, LAAM doses were well tolerated by most patients. CONCLUSION: Induction with low and medium LAAM doses can be safely and effectively achieved within 7 days. Induction with higher LAAM doses can be safely achieved within 17 days, but may result in greater rates of patient dropout and opioid agonist adverse effects. Therefore, higher doses should be approached more slowly.

Adult↗
PubMed1988

Induction and reversal of depression, anxiety, and hostility.

Anxiety, hostility, and depression were induced and reversed by use of the Velton (1968) Mood Induction Procedure. Forty subjects were assigned randomly to one of four induction groups: Anxiety, Depression, Hostility, or Neutral. Mood states, measured by the Multiple Affect Adjective Check List (MAACL) were obtained before induction, after induction, and after reversal of moods. All mood induction treatments increased levels of all moods, but did not differentially increase a specific mood. Induced moods were reversed by using statements opposite to the induction ones. Mood induction was not correlated with previously administered Internal-External Locus of Control and Profile of Mood States questionnaires, but a high baseline MAACL score was correlated with low mood induction. Questions amenable to future research were raised.

Adolescent↗
PubMed2000

Intravenous prostaglandin for induction of labour.

BACKGROUND: Intravenous prostaglandin E2 and F2 alpha can be used to induce labour. The use of intravenous prostaglandins in this context has been limited by perceived unacceptable maternal side effect profiles. This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. OBJECTIVES: To determine the effects of intravenous prostaglandin for third trimester cervical ripening or induction of labour. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register, The Cochrane Controlled Trials Register and bibliographies of relevant papers. SELECTION CRITERIA: The criteria for inclusion included the following: (1) clinical trials comparing intravenous prostaglandin used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods; (2) random allocation to the treatment or control group; (3) adequate allocation concealment; (4) violations of allocated management not sufficient to materially affect conclusions; (5) clinically meaningful outcome measures reported; (6) data available for analysis according to the random allocation; (7) missing data insufficient to materially affect the conclusions. DATA COLLECTION AND ANALYSIS: A strategy has been developed to deal with the large volume and complexity of trial data relating to labour induction. This involves a two-stage method of data extraction. The initial data extraction is done centrally, and incorporated into a series of primary reviews arranged by methods of induction of labour, following a standardised methodology. The data will then be extracted from the primary reviews into a series of secondary reviews, arranged by category of woman. To avoid duplication of data in the primary reviews, the labour induction methods have been listed in a specific order, from one to 25. Each primary review includes comparisons between one of the methods (from two to 25) with only those methods above it on the list. MAIN RESULTS: Thirteen trials were eligible for inclusion in this review. Two trials (comprising 400 women) compared intravenous prostaglandin E2 to intravenous oxytocin, a further seven trials (comprising 590 women) compared intravenous prostaglandin F2 alpha to intravenous oxytocin. Two trials (comprising 115 women) each randomised women to one of three treatment arms namely intravenous oxytocin or intravenous prostaglandin F2 alpha or prostaglandin E2. One trial reported a comparison of combined oxytocin and prostaglandin F2 alpha and oxytocin alone in 20 women and lastly one trial compared extra amniotic prostaglandin E2 versus intravenous prostaglandin E2 (40 women). The use of intravenous prostaglandin was associated with higher rates of uterine hyperstimulation with changes in the fetal heart rate (relative risk (RR) 6.76, 95% confidence interval (CI) 1.23-37.11) and without (RR 4.25, 95%CI 1.48-12.24) compared to oxytocin. Use of prostaglandins was also associated with significantly more maternal side effects (gastrointestinal, thrombophlebitis and pyrexia, RR 3.75, 95% CI 2.46-5.70) than oxytocin. Prostaglandin was no more likely to result in vaginal delivery than oxytocin (RR 0.85, 95% CI 0.61-1.18). No significant differences emerged from subgroup analysis or from the trials comparing combination oxytocin/prostaglandin F2 alpha and oxytocin or extra amniotic versus intravenous prostaglandin E2. REVIEWER'S CONCLUSIONS: Intravenous prostaglandin is no more efficient than intravenous oxytocin for the induction of labour but its use is associated with higher rates of maternal side effects and uterine hyperstimulation than oxytocin. No conclusions can be drawn form the comparisons of combination of prostaglandin F2 alpha and oxytocin compared to oxytocin alone or extra amniotic and intravenous prostaglandin E2.

Clinical Trials as Topic↗
PubMed2001

Acupuncture for induction of labour.

BACKGROUND: This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. The use of complementary therapies is rising and some women look to complementary therapies during pregnancy and childbirth to be used alongside conventional medical practice. Acupuncture involves the insertion of very fine needles into specific points of the body. The limited observational studies to date suggest acupuncture for induction of labour appears safe, has no known teratogenic effects, and may be effective. The evidence regarding the clinical effectiveness of this technique is limited. OBJECTIVES: To determine the effects of acupuncture for third trimester cervical ripening or induction of labour. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and bibliographies of relevant papers. SELECTION CRITERIA: The criteria for inclusion included the following: (1) clinical trials comparing acupuncture used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods; (2) random allocation to the treatment or control group; (3) adequate allocation concealment; (4) violations of allocated management not sufficient to materially affect conclusions; (5) clinically meaningful outcome measures reported; (6) data available for analysis according to the random allocation; (7) missing data insufficient to materially affect the conclusions. DATA COLLECTION AND ANALYSIS: A strategy has been developed to deal with the large volume and complexity of trial data relating to labour induction. This involves a two-stage method of data extraction. The initial data extraction is done centrally, and incorporated into a series of primary reviews arranged by methods of induction of labour, following a standardised methodology. The data will then be extracted from the primary reviews into a series of secondary reviews, arranged by category of woman. To avoid duplication of data in the primary reviews, the labour induction methods have been listed in a specific order, from one to 25. Each primary review includes comparisons between one of the methods (from two to 25) with only those methods above it on the list. MAIN RESULTS: No trials met the inclusion criteria for the systematic review. REVIEWER'S CONCLUSIONS: There is a need for a well designed randomised controlled trial to evaluate the role of acupuncture to induce labour.

Acupuncture↗
PubMed2001

Oral prostaglandin E2 for induction of labour.

BACKGROUND: This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. OBJECTIVES: To determine the effects of oral prostaglandin E2 for third trimester induction of labour. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and bibliographies of relevant papers. Date of last search: December 2000. SELECTION CRITERIA: The criteria for inclusion included the following: (1) clinical trials comparing oral prostaglandin E2 used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods; (2) random allocation to the treatment or control group; (3) adequate allocation concealment; (4) violations of allocated management not sufficient to materially affect conclusions; (5) clinically meaningful outcome measures reported; (6) data available for analysis according to the random allocation; (7) missing data insufficient to materially affect the conclusions. DATA COLLECTION AND ANALYSIS: A strategy has been developed to deal with the large volume and complexity of trial data relating to labour induction. This involves a two-stage method of data extraction. The initial data extraction is done centrally, and incorporated into a series of primary reviews arranged by methods of induction of labour, following a standardised methodology. The data will then be extracted from the primary reviews into a series of secondary reviews, arranged by category of woman. To avoid duplication of data in the primary reviews, the labour induction methods have been listed in a specific order, from one to 25. Each primary review includes comparisons between one of the methods (from two to 25) with only those methods above it on the list. MAIN RESULTS: There were 19 studies included in the review. Of these 15 included a comparison using either oral or intravenous oxytocin with or without amniotomy. The quality of studies reviewed was not high. Only seven studies had clearly described allocation concealment. Only two studies stated that providers and/or participants were blinded to treatment group. For the outcome of vaginal delivery not achieved within 24 hours, in the composite comparison of oral PGE2 versus all oxytocin treatments (oral and intravenous, with and without amniotomy), there was a trend favoring oxytocin treatments (relative risk (RR) 1.97, 95% confidence interval (CI) 0.86 to 4.48). For the outcome of cesarean section, in the comparison of PGE2 versus no treatment or placebo, PGE2 was favored (relative risk (RR) 0.54, 95% confidence interval (CI) 0.29,0.98). Otherwise, there were no significant differences between groups for this outcome. Oral prostaglandin was associated with vomiting across all comparison groups. REVIEWER'S CONCLUSIONS: Oral prostaglandin consistently resulted in more frequent gastrointestinal side effects, in particular vomiting, compared with the other treatments included in this review. There were no clear advantages to oral prostaglandin over other methods of induction of labour.

Administration, Oral↗
PubMed2001

Castor oil, bath and/or enema for cervical priming and induction of labour.

BACKGROUND: Castor oil, a potent cathartic, is derived from the bean of the castor plant. Anecdotal reports, which date back to ancient Egypt have suggested the use of castor oil to stimulate labour. Castor oil has been widely used as a traditional method of initiating labour in midwifery practice. Its role in the initiation of labour is poorly understood and data examining its efficacy within a clinical trial are limited. This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. OBJECTIVES: To determine the effects of castor oil or enemas for third trimester cervical ripening or induction of labour in comparison with other methods of cervical ripening or induction of labour. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and bibliographies of relevant papers. Last searched: November 2000. SELECTION CRITERIA: (1) clinical trials comparing castor oil, bath or enemas used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods; (2) random allocation to the treatment or control group; (3) adequate allocation concealment; (4) violations of allocated management not sufficient to materially affect conclusions; (5) clinically meaningful outcome measures reported; (6) data available for analysis according to the random allocation; (7) missing data insufficient to materially affect the conclusions. DATA COLLECTION AND ANALYSIS: A strategy has been developed to deal with the large volume and complexity of trial data relating to labour induction. This involves a two-stage method of data extraction. MAIN RESULTS: In the one included study of 100 women, which compared a single dose of castor oil versus no treatment, no difference was found between caesarean section rates (relative risk (RR) 2.31, 95% CI 0.77, 6.87). No data were presented on neonatal or maternal mortality or morbidity. There was no difference between either the rate of meconium stained liquor (RR 0.77, 95% CI 0.25,2.36) or Apgar score < 7 at 5 minutes (RR 0.92, 95% CI 0.02,45.71) between the two groups. The number of participants was small hence only large differences in outcomes could have been detected. All women who ingested castor oil felt nauseous. REVIEWER'S CONCLUSIONS: The only trial included in this review attempts to address the role of castor oil as an induction agent. The trial was small and of poor methodological quality. Further research is needed to attempt to quantify the efficacy of castor oil as an induction agent.

Castor Oil↗
PubMed2006

Corticosteroids for cervical ripening and induction of labour.

BACKGROUND: The role of corticosteroids in the process of labour is not well understood. Animal studies have shown the importance of cortisol secretion by the fetal adrenal gland in initiating labour in sheep. Infusion of glucocorticosteroids into the fetus has also shown to induce premature labour in sheep. Given these studies it has been postulated that corticosteroids will promote the induction of labour in women. This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. OBJECTIVES: To determine the effects of corticosteroids for third trimester cervical ripening or induction of labour in comparison with other methods of cervical priming or induction of labour. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (December 2005) and bibliographies of relevant papers. SELECTION CRITERIA: Clinical trials of corticosteroids for third trimester cervical ripening or labour induction. DATA COLLECTION AND ANALYSIS: A strategy was developed to deal with the large volume and complexity of trial data relating to labour induction. This involved a two-stage method of data extraction. We assessed trial quality. We contacted study authors for additional information. We collected adverse effects information from the trials. MAIN RESULTS: Only one small trial (66 women) was included. The primary outcome vaginal birth within 24 hours was not reported. No benefit of intramuscular administration of corticosteroids with intravenous oxytocin was found when compared with oxytocin alone. However, given the small size of this trial this result should be interpreted cautiously. AUTHORS' CONCLUSIONS: The effectiveness of corticosteroids for induction of labour is uncertain. This method of induction of labour is not commonly used and so further research in this area is probably unwarranted.

Administration, Topical↗
PubMed2002

Phase II study of induction chemotherapy with paclitaxel, ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: This Phase II trial was conducted to determine the response rate, particularly of the primary sites, tolerability, and toxicity of induction chemotherapy of paclitaxel, ifosfamide, and carboplatin for patients with previously untreated locally advanced squamous cell carcinoma of the head and neck (SCCHN). We also hypothesized that improved complete response (CR) rates with the induction chemotherapy may render better survival rates with subsequently delivered definitive local treatment. METHODS: All eligible patients with locally advanced SCCHN received two courses of induction chemotherapy and underwent repeated head and neck examination and computed tomography or magnetic resonance imaging scans. If the patients achieved responses (CR or partial [PR]), they received two more courses of chemotherapy before undergoing definitive local treatment. Induction chemotherapy consisted of paclitaxel (T; 175 mg/m(2) in a 3-hour infusion) on Day 1, ifosfamide (I; 1000 mg/m(2) in a 2-hour infusion) on Days 1-3 with intravenous mesna (200 mg/m(2) before and 400 mg/m(2) after ifosfamide), and carboplatin (C) using the Calvert formula for the area under the plasma concentration-versus-time curve of 6 on Day 1, repeated every 3-4 weeks. Prophylactic hematopoietic growth factors or antibiotics were not used in this study. Definitive local treatment was given based on the investigators' preference. RESULTS: Fifty-four patients were registered and 52 patients were assessable for response to induction chemotherapy; 2 were not evaluable. After four courses of induction chemotherapy, the CR rates of the primary and lymph node sites were 60%, and 41%, respectively. For both primary and lymph node sites, there were 31% CRs and 50% PRs with an overall response rate of 81%. Five (9%) patients developed neutropenic fever, all of whom recovered with antibiotic therapy. Two (4%) patients had infection without neutropenia and recovered without any complication. Grade 3/4 thrombocytopenia and anemia occurred in three (6%) and four (7%) patients, respectively. Grade 3/4 fatigue developed in four (7%), arthralgia/myalgia in two (4%), peripheral neuropathy in two (4%), and orthostatic hypotension in two (4%) patients. One patient died of severe anaphylaxis although a maximized resuscitation effort was made. With a median follow-up of 22 months, the organ preservation rate was about 81% (42 of 52 patients). Although survival rates were not primary end points in this study, with a median follow-up of 22 months, 43 (83%) patients are still alive. Overall 1 and 2-year survival rates were 88% and 82%, respectively. Disease-free 1 and 2-year survival rates were 88% and 77% respectively. CONCLUSIONS: TIC induction chemotherapy is associated with a high CR rate at the primary sites and with excellent survival and organ preservations rates with subsequently delivered definitive local therapy. The regimen was also well tolerated in the majority of patients. The TIC regimen should be developed further in the context of induction chemotherapy followed by concomitant chemoradiotherapy or with specific molecular targeted agents.

Adult↗
PubMed1982

Multihormonal induction of alpha 2u-globulin in an established rat hepatoma cell line.

A subclone of the FU5-5 rat hepatoma cell line has been isolated which is inducible more than several hundred fold for the 20,000 dalton form of the major rat urinary protein alpha 2u-globulin. The basal relative synthetic rate (RSR) in growth medium containing 10% fetal calf serum was less than 2 X 10(-6) of total protein synthesis. Both dexamethasone and insulin were necessary for induction, and yielded a maximum induced RSR of 4-8 X 10(-3). Triiodothyronine (T3), dihydrotestosterone (DHT), rat growth hormone (GH), and estrogen, all of which have been shown to influence the induction of alpha 2u-globulin in the intact rat, were without effect on the cell line. A factor present in fetal calf serum was also necessary for maximum induction, since dexamethasone plus insulin in serum-free medium raised the RSR to only 3 X 10(-5); exogenous T3, GH, and DHT could not substitute for this serum factor. The kinetics of induction by dexamethasone were slow, with a lag of approximately 48 hr followed by a period of increasing RSR for 6-20 days. Removal of dexamethasone from induced cells led to an exponential decline in the RSR (t 1/2 15 hr). The concentrations of dexamethasone and insulin that could yield half maximum induction were 5 X 10(-8)M and 3 X 10(-11)M, respectively. Higher concentrations of insulin, although still in physiological range (10(-9)M), inhibited induction. At yet higher insulin levels, beyond the physiological range, alpha 2u-globulin synthesis returned to maximum values. The lack of DHT, T3, and GH requirement for alpha 2u-globulin induction in this cell line may mean that a regulatory aberrancy has occurred in this transformed cell line, or, alternatively, that these hormones act indirectly in the intact animal. This cell line should prove useful for the study of the molecular events associated with alpha 2u-globulin induction and for genetic approaches to the problem of multihormonal regulation of gene expression.

Alpha-Globulins↗
PubMed2002

Dopamine transporter-dependent induction of C-Fos in HEK cells.

The psychostimulants cocaine and amphetamine increase expression of the immediate early gene (IEG) c-fos indirectly, via D1 dopamine receptor activation. To determine whether dopamine transporter substrates and inhibitors can affect c-Fos expression directly, we investigated their effects on c-Fos protein and c-fos mRNA in HEK-293 (HEK) cells transfected with the human dopamine transporter (hDAT). In untransfected HEK cells, methylphenidate and cocaine produced a small but statistically significant increase in c-Fos, whereas dopamine and amphetamine did not. In hDAT cells, DAT substrates (dopamine, amphetamine) increased c-Fos immunoreactivity 6- and 3-fold (respectively). The DAT inhibitors cocaine, methylphenidate, and bupropion also increased c-Fos approximately 3-fold in hDAT cells. If coincubated with dopamine, the inhibitors attenuated dopamine-induced c-Fos in hDAT cells. The magnitude of c-fos mRNA induction by substrates and inhibitors paralleled induction of c-Fos protein immunoreactivity. The results indicate that substrates or inhibitors of the DAT can trigger induction of IEG expression in the absence of D1 dopamine receptor. For substrates, IEG induction is DAT-dependent, but for certain DAT inhibitors the cellular response can be elicited in the absence of the DAT in HEK cells. Oxidative stress may partly, but not fully, account for the DA-induced c-Fos induction as an inhibitor of oxidative stress Trolox C, attenuated DA-induced c-Fos induction. Protein kinase C (PKC) may also partially account for c-Fos induction as a specific inhibitor of PKC Bisindolylmaleimide I (BIS) attenuated DA-induced c-Fos by 50%. DAT substrate and inhibitor effects on IEGs, other fos-related antigens, and possible mechanisms that contribute to c-Fos induction warrant investigation in presynaptic neurons as a potential contribution to the long-term effects of psychostimulants.

Amphetamine↗
PubMed1998

Temporal restriction of MyoD induction and autocatalysis during Xenopus mesoderm formation.

In Xenopus, the activation of the myogenic determination factors MyoD and Myf-5 in the muscle-forming region of the embryo occurs in response to mesoderm-inducing factors (MIFs). Different members of the FGF, TGF-beta, and Wnt protein families have been implicated in this process, but how MIFs induce the myogenic regulators is not known. For MyoD, the induction process may serve to locally stabilize a transient burst of ubiquitous transcription at the midblastula transition, possibly by triggering MyoD's autocatalytic loop. Here we have sought to distinguish separate activating functions during MyoD induction by analyzing when MyoD responds to different MIF signaling or to MyoD autoactivation. We show that MyoD induction depends on the developmental age of the induced cells, rather than on the type or time point of inducer application. At the permissive time, de novo MyoD induction by Activin requires less than 90 min, arguing for an immediate response, rather than a series of inductive events. MyoD autoactivation is direct, but subject to the same temporal restriction as MyoD induction by MIF signaling. Further evidence implicating MyoD autocatalysis as an essential component of the induction process comes from the observation that both autocatalysis and induction of MyoD are selectively repressed by a dominant-negative MyoD mutant. In summary, our observations let us conclude that MyoD's expression domain in the embryo results from an interplay of timed changes in cellular competence, pleiotropic signaling pathways, and autocatalysis.

Activins↗
PubMed2000

Determining relative estrogenicity by quantifying vitellogenin induction in rainbow trout liver slices.

Precision cut tissue slices, by modeling the entire organ, are a valuable tool for studying protein induction or inhibition by test chemicals. This manuscript describes parameters to quantify relative estrogenicity of chemicals in rainbow trout liver slices by measuring vitellogenin (Vg) induction, a well-characterized biomarker of estrogen receptor signal transduction. Hank's medium (phenol-red free) supplemented with Hepes, sodium bicarbonate, and 1% bovine serum albumin was utilized. The experimental parameters were optimized using 1000 nM 17beta-estradiol, a potent estrogen in rainbow trout that induces Vg production in vivo. The addition of trout serum and retention of the media was essential, probably to allow for the accumulation of Vg in the slices and media. Histological examination and ATP analyses indicated no toxicity in control or 17beta-estradiol-treated liver slices after 120 h. Induction was 4-fold greater with 25% serum containing media compared to media with 10% serum. We observed Vg induction as great as 500-fold over controls at 96 h in liver slices and media containing 25% serum and 1000 nM 17beta-estradiol. Controls without 17beta-estradiol, incubated in media with 10 or 25% serum, exhibited no detectable Vg production, indicating that the induction seen was not from the media or serum. We observed that 48 h was required for significant Vg induction in the media and liver slices. Maximum induction in slices occurred at 96 h, whereas media Vg levels continued to increase to 120 h, suggesting a time delay between Vg production and excretion by the liver. The feasibility of this model to detect weak environmental estrogens was determined with 0-250 microM o,p'DDE and bisphenol A. Both compounds induced Vg in this model with EC50 values of 10(4) and 2x10(5) higher than E(2), respectively. Our results indicate the importance of media, serum, and time selection for optimal Vg induction. This model allows for the determination of relative estrogenicity of chemicals in a controlled in vitro system while utilizing the advantages of precision cut slice technology.

Adenosine Triphosphate↗