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PubMed2002

Impact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children's Cancer Group.

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF) administered during acute myelogenous leukemia (AML) induction affects hematopoietic and nonhematopoietic toxicity, length and outcome of induction therapy, event-free survival, overall survival, and prognostic significance of the day 7 bone marrow. PATIENTS AND METHODS: In Children's Cancer Group study 2891, patients were given intensively timed induction with G-CSF (n = 254) after accrual for the regimen without G-CSF (n = 258) was met. RESULTS: Time to neutropenic recovery after induction courses 1 and 2 was significantly shorter for patients who received G-CSF. Times to platelet recovery were similar regardless of G-CSF use. Effects on incidence of grades 3 and 4 toxicities, infections, or fatal infections were not observed. Use of G-CSF reduced the median length of induction by 9 days and hospital stay by 6 days. Induction remission rates, overall survival, and event-free survival were similar with and without G-CSF. Day 7 bone marrow was prognostic of better long-term outcome. Patients with hypercellular day 7 marrow who received G-CSF had a higher remission rate and event-free survival than patients who did not receive G-CSF. CONCLUSIONS: The incidence of severe toxic event and infection, induction remission rate, overall survival, and event-free survival were comparable regardless of G-CSF use. Use of G-CSF decreased neutropenia duration, hospital stay, and length of induction. Patients with hypercellular day 7 bone marrow who received G-CSF had an induction remission rate and event-free survival superior to those of patients who did not receive G-CSF.

Acute Disease↗
PubMed2003

Distinct ultraviolet-signaling pathways in bean leaves. DNA damage is associated with beta-1,3-glucanase gene induction, but not with flavonoid formation.

The enzyme beta-1,3-glucanase (betaGlu) was found to be strongly induced by ultraviolet (UV-B; 280-320 nm) radiation in primary leaves of French bean (Phaseolus vulgaris). This was demonstrated on the level of gene transcription, protein synthesis, and enzyme activity and was due to the expression of bean class I betaGlu (betaGlu I). In contrast to other proteins of the family of pathogenesis-related proteins, the induction of betaGlu I by UV correlated with the formation of photoreversible DNA damage, i.e. pyrimidine dimer formation. In conditions that allowed photorepair of this damage, betaGlu I induction was blocked. Therefore, UV-induced DNA damage seems to constitute a primary signal in the pathway leading to the induction of the betaGlu I gene(s). The induction was a local response because in partly irradiated leaves betaGlu I was selectively found in leaf parts exposed to UV. Although short wavelength UV (lambda < 295 nm) was most efficient in betaGlu I induction, longer wavelength UV (lambda > 295 nm) as present in natural radiation was still effective. In contrast to UV induction of betaGlu I, the induction of flavonoids in bean leaves was optimally triggered by much more moderate fluences from the UV wavelength range no longer effective in betaGlu I induction. UV induction of the flavonoid pathway shows no correlation with DNA damage and thus should be mediated via a different signal transduction pathway.

Base Sequence↗
PubMed1991

Comparison of the T lymphocyte-dependent induction of angiotensin-converting enzyme and leucine aminopeptidase in cultured human monocytes.

The T lymphocyte-mediated induction of angiotensin-converting enzyme (ACE) in cultured autologous peripheral blood monocytes has been proposed as a model system for the investigation of the in vivo induction of ACE in the monocyte-derived granuloma epithelioid cells of some granulomatous diseases such as sarcoidosis. The studies described here were designed to evaluate the specificity of the model system by comparing the parameters for induction of ACE with those for the induction of another monocyte metallo-ecto-peptidase, leucine aminopeptidase (LAP). The concentration of LAP in freshly isolated monocytes was 0.09 mU/10(6) monocytes (s.e.m. 0.04) and increased to a maximal value of 0.19 mU/10(6) monocytes (s.e.m. 0.32) after 3 days when monocytes were cultured alone. ACE was not detectable in freshly isolated monocytes. However, after 6 days of culture, monocytes contained 0.22 mU ACE/10(6) monocytes (s.e.m. 0.04). Comparison of the levels of ACE and LAP induced during culture of monocytes alone indicated that the induction of these two enzymes were correlated. The induction of both enzymes was further enhanced by the presence of T lymphocytes in a dose-dependent manner. At 4 x 10(6) T lymphocytes per culture, ACE levels increased to 1.81 mU/10(6) monocytes (s.e.m. 0.24) and LAP levels to 1.03 mU/10(6) monocytes (s.e.m. 0.35). The enhancement of ACE activity required autologous lymphocytes, while heterologous T lymphocytes were equally effective in inducing LAP. Comparison of the levels of ACE and LAP induced during coculture of autologous T lymphocytes and monocytes from 21 independent donors, demonstrated no correlation between the induction of ACE and LAP. These data indicate that, although T lymphocytes also enhance the induction of LAP, the underlying mechanism must differ from that of ACE induction.

Cells, Cultured↗
PubMed1971

Induction specificity and catabolite repression of the early enzymes in camphor degradation by Pseudomonas putida.

The ability of bornane and substituted bornanes to induce the early enzymes for d(+)-camphor degradation and control of these enzymes by catabolite repression were studied in a strain of a Pseudomonas putida. Bornane and 20 substituted bornane compounds showed induction. Of these 21 compounds, bornane and 8 of the substituted bornanes provided induction without supporting growth. Oxygen, but not nitrogen, enhanced the inductive potency of the unsubstituted bornane ring. All bornanedione isomers caused induction, and those with substituents on each of the three consecutive carbon atoms, including the methyl group at the bridgehead carbon, showed induction without supporting growth. Although it was not possible to obtain experimental data for a case of absolute gratuitous induction by compounds not supporting growth, indirect evidence in support of gratuitous induction is presented. It is proposed that the ability of P. putida to tolerate the unusually high degree of possible gratuitous induction observed for camphor catabolism may be related to the infrequent occurrence of bicyclic ring structures in nature. Survival of an organism with a broad specificity for gratuitous induction is discussed. Glucose and succinate, but not glutamate, produced catabolite repression of the early camphor-degrading enzymes. Pathway enzymes differ in their degree of sensitivity to succinate-provoked catabolite repression. The ability of a compound to produce catabolite repression is not, however, directly related to the duration of the lag period (diauxic lag) between growth on camphor and growth on the repressing compound.

Alcohol Oxidoreductases↗
PubMed1969

Synergistic and product induction of the enzymes of tryptophan metabolism in Pseudomonas acidovorans.

The process of induction of tryptophan oxygenase in Pseudomonas acidovorans is typical of many microbial enzyme induction systems, in that it (i) requires cell multiplication and de novo protein synthesis, (ii) is subject to catabolite repression, (iii) results in the formation of a stable enzyme, whose level, upon removal of inducer, is diluted out by cell proliferation, and (iv) exhibits product induction. l-Kynurenine was more effective than l-tryptophan as an inducer of both tryptophan oxygenase and the second enzyme of the pathway, kynurenine formamidase. The occurrence of product induction of these two enzymes by their common metabolite eliminated the possibility of sequential induction of these enzymes. dl-5-Fluorotryptophan, nonmetabolizable and devoid of any inducing activity, resulted in a concentration-dependent inhibition of the l-tryptophan-mediated induction of tryptophan oxygenase; kynurenine formamidase induction, however, was not influenced by the presence of dl-5-fluorotryptophan. dl-7-Azatryptophan, also nonmetabolizable and completely inactive as an inducer, acted synergistically with l-tryptophan and superinduced tryptophan oxygenase levels. When induction was conducted in a medium containing only l-tryptophan and 7-azatryptophan as inducing agents, then tryptophan oxygenase induction was enhanced, whereas the kynurenine formamidase level was essentially unchanged. These data indicate that various inducing conditions affect the relative proportions of tryptophan oxygenase and kynurenine formamidase, and thus indicate noncoordinate regulation of these enzyme activities.

Amidohydrolases↗
PubMed1993

Biphasic ordered induction of heme synthesis in differentiating murine erythroleukemia cells: role of erythroid 5-aminolevulinate synthase.

During dimethyl sulfoxide (DMSO)-stimulated differentiation of murine erythroleukemia (MEL) cells, one of the early events is the induction of the heme biosynthetic pathway. While recent reports have clearly demonstrated that GATA-1 is involved in the induction of erythroid cell-specific forms of 5-aminolevulinate synthase (ALAS-2) and porphobilinogen (PBG) deaminase and that cellular iron status plays a regulatory role for ALAS-2, little is known about regulation of the remainder of the pathway. In the current study, we have made use of a stable MEL cell mutant (MEAN-1) in which ALAS-2 enzyme activity is not induced by DMSO, hexamethylene bisacetamide (HMBA), or butyric acid. In this cell line, addition of 2% DMSO to growing cultures results in the normal induction of PBG deaminase and coproporphyrinogen oxidase but not in the induction of the terminal two enzymes, protoporphyrinogen oxidase and ferrochelatase. These DMSO-treated cells did not produce mRNA for beta-globin and do not terminally differentiate. In addition, the cellular level of ALAS activity declines rapidly after addition of DMSO, indicating that ALAS-1 must turn over rapidly at this time. Addition of 75 microM hemin alone to the cultures did not induce cells to terminally differentiate or induce any of the pathway enzymes. However, the simultaneous addition of 2% DMSO and 75 microM hemin caused the cells to carry out a normal program of terminal erythroid differentiation, including the induction of ferrochelatase and beta-globin. These data suggest that induction of the entire heme biosynthetic pathway is biphasic in nature and that induction of the terminal enzymes may be mediated by the end product of the pathway, heme. We have introduced mouse ALAS-2 cDNA into the ALAS-2 mutant cell line (MEAN-1) under the control of the mouse metallothionein promoter (MEAN-RA). When Cd and Zn are added to cultures of MEAN-RA in the absence of DMSO, ALAS-2 is induced but erythroid differentiation does not occur and cells continue to grow normally. In the presence of metallothionein inducers and DMSO, the MEAN-RA cells induce in a fashion similar to that found with the wild-type 270 MEL cells. Induction of the activities of ALAS, PBG deaminase, coproporphyrinogen oxidase, and ferrochelatase occurs. In cultures of MEAN-RA where ALAS-2 had been induced with Cd plus Zn 24 h prior to DMSO addition, onset of heme synthesis occurs more rapidly than when DMSO and Cd plus Zn are added simultaneously. This study reveals that induction of ALAS-2 alone is not sufficient to induce terminal differentiation of the MEAN-RA cells, and it does not appear that ALAS-2 alone is the rate-limiting enzyme of the heme biosynthetic pathway during MEL cell differentiation.

5-Aminolevulinate Synthetase↗
PubMed1983

Epithelial induction of osteogenesis in embryonic chick mandibular mesenchyme: a possible role for basal lamina.

The initiation of osteogenesis at 7 days in the embryonic chick mandibular mesenchyme depends on an epithelial induction in the mandible to day 4. This article reviews a series of experiments conducted to study the nature of this inductive mechanism. Transfilter tissue recombinations were used to determine whether direct tissue apposition was required for induction. Ultrastructural studies of the epithelial-mesenchymal interface were conducted to see if direct epithelial-mesenchymal cell-cell contacts occurred during the inductive stage in vivo. Epithelial cells were cultured on Millipore filters for 28 days and allowed to deposit extracellular products. These products were tested for inductive activity. Findings from these three sets of experiments were discussed with respect to the inductive mechanism. Our results indicate that the induction is not mediated by a diffusible substance and that direct apposition of the two tissues is required. The mechanism of induction, however, does not require direct epithelial-mesenchymal cell to cell contacts. This suggests that a nondiffusible component of the extracellular matrix may be involved. Epithelial extracellular products are inductively active and have the appearance of basal lamina. The active component of the extracellular product is proteinaceous, perhaps collagen, and appears to be situated in the epithelial basal lamina. The role of basal lamina in epithelial-mesenchymal interactions is discussed.

Animals↗
PubMed1993

Effects of female hormones and 3,5,3'-triiodothyronine or dexamethasone on induction of epidermal growth factor and proteinases F, D, A, and P in the submandibular glands of hypophysectomized male mice.

The effects of progesterone (Pro), 5 alpha-dihydrotestosterone (DHT), 17 beta-estradiol (E2), T3, and dexamethasone (Dex), given alone or in combination, on induction of epidermal growth factor (EGF) and proteinase isozymes in the submandibular glands of hypophysectomized mice were examined. Each hormone, except E2, acting alone had essentially comparable inductive effects on EGF concentrations and on total proteinase activity. E2 alone had no inductive effect at all. Pro acted synergistically with T3, but its inductive effect was diminished when given with Dex. E2 was not synergistic with T2, and it inhibited the effect of Dex; it also partially blocked the action of DHT on induction of proteinase activity but not of EGF. Simultaneous administration of all five hormones restored total proteinase activity completely but EGF levels to only 50% of values for intact males, respectively. Submandibular proteinases were resolved by isoelectric focusing into four isozymes: proteinase F (pI 4.8), proteinase D (pI 5.8), proteinase A (pI 6.2), and proteinase P (pI 10.0). Pro alone slightly increased levels of proteinase F but greatly raised levels of the other three isozymes. This inductive action was augmented when Pro was given with T3 but blocked when it was given with Dex. E2 alone not only failed to induce any of the isozymes, but even further reduced levels of proteinase F. It also decreased the inductive effects of T3 on these isozymes, and with Dex completely blocked induction of proteinases D, A, and P. E2 plus DHT suppressed proteinase F levels and only induced proteinase A. All five hormones together reestablished the isozyme profile seen in intact males. These results show that Pro by itself is as capable as androgens, thyroid hormone, or glucocorticoid in regulating expression of these submandibular polypeptides, and that its action can be modulated by other pituitary-dependent hormones. In addition, they demonstrate that E2 does not regulate their expression, and that it has an inhibitory effect on the inductive action of other hormones. Last, they indicate that these various hormones may regulate expression of EGF and of each of the individual proteinase isozymes differently.

Animals↗
PubMed1987

Differential sensitivity of HTC and Fu5-5 cells for induction of tyrosine aminotransferase by 3',5'-cyclic adenosine monophosphate.

The two independently derived hepatoma cell lines (HTC and Fu5-5) have previously been shown to display different sensitivities for the induction of tyrosine aminotransferase (TAT) enzyme activity and mRNA levels by glucocorticoids with the enzyme being half-maximally induced at approximately 7-fold higher concentrations of dexamethasone in HTC cells than in Fu5-5 cells. In the present study we investigated the induction of TAT activity by cAMP in order to see whether the difference is limited to the steroidal induction. Using the stable cAMP derivative (8-(4-chlorophenylthio)-cAMP) as an inducer, we found that a 6-fold higher cAMP concentration was needed in HTC cells to achieve the same extent of enzyme induction as in Fu5-5 cells. The induction of TAT enzyme activity could be accounted for by an increased amount of TAT mRNA. Further experiments involving sequential addition of both inducers in general showed a synergism of steroids and cAMP for TAT induction in HTC cells only at submaximal concentrations of steroid; in Fu5-5 cells, the occurrence of synergism depended on the order of addition of inducers. The maximal response in HTC cells was limited to the value that could be achieved by induction with steroid alone. In Fu5-5 cells, however, the steroid response could be augmented when cAMP was added to cells already maximally induced by steroid. This demonstrates that the effect of a combination of cAMP and steroids depends on their concentration, the sequence of their addition, and the rat hepatoma cell line used. Collectively the data suggest that a common pretranslational event determines the differential sensitivity of TAT induction by glucocorticoids and by cAMP in HTC and Fu5-5 cells. Furthermore a second, or possibly the same, common event also regulates the maximum level of TAT induction that is obtainable under most conditions with glucocorticoids and/or cAMP.

Animals↗
PubMed1993

Dose-response relationships for the induction of P450 2B by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzne (TCPOBOP) in rat and cultured rat hepatocytes.

1. The dose-response relationships for hepatic CYP2B induction by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) were examined in the male F344/NCr rat. TCPOBOP, administered for 14 days at 0-1000 ppm in the diet, caused concentration-dependent induction of hepatic CYP2B1 protein and RNA, and of CYP2B-mediated catalytic activities (benzyloxy- and pentoxyresorufin O-dealkylation, and testosterone 16 beta-hydroxylation). ED50 values for CYP2B induction were > or = 300 ppm dietary TCPOBOP. The maximal inductions observed were 66-88% of those resulting from exposure of the rats to 500 ppm dietary phenobarbital. 2. The EC50 values for hepatic CYP2B induction were 1.5-3.0 microM (based on serum TCPOBOP) and 15-20 mumol/kg liver. 3. The maximal inductions of isozymes of the CYP3A subfamily, of microsomal epoxide hydrolase, and of glutathione S-transferases Ya/Yc and Yb1/Yb2 in rats exposed to TCPOBOP were 58-74% of those resulting from exposure of the rats to 500 ppm dietary phenobarbital. 4. The ED50 value for induction of benzyloxyresorufin O-dealkylation in cultured rat hepatocytes by TCPOBOP was determined to be 0.93 microM. The maximal induction of this activity caused by TCPOBOP was 87% of the maximum increases caused by phenobarbital. 5. The results indicate that TCPOBOP is a highly effective phenobarbital-type inducer in the rat when administered in the diet for 2 weeks at 1000 ppm. When extent of induction is related to serum total xenobiotic level, TCPOBOP would appear to be at least as potent as, if not more potent than, phenobarbital in the rat.

Animals↗
PubMed1999

A phase I/II study of intensive dose escalation of cytarabine in combination with idarubicin and etoposide in induction and consolidation treatment of adult acute myeloid leukemia. Australian Leukaemia Study Group (ALSG).

To determine the safety and efficacy of the combination of idarubicin, cytarabine and etoposide ("ICE") for induction and consolidation treatment of acute myeloid leukemia (AML), and of dose-intensification of cytarabine in this setting, 54 previously untreated patients in three cohorts were studied by sequential dose escalation of cytarabine, in combination with standard doses of idarubicin and etoposide. Cytarabine was given to Cohort 1 at the conventional dosage of 100 mg/m2 per day by continuous infusion for 7 days in induction and 5 days in consolidation; to Cohort 2 at high-dose (HiDAC) (3 g/m2 intravenously twice daily on days 1, 3, 5 and 7) during induction with conventional dosage during consolidation; to Cohort 3 HiDAC was given for both induction and consolidation. In addition, Cohort 3 patients received lenograstim (Granocyte; rHuG-CSF) after both induction and consolidation courses. We found that there was no significant difference between the three cohorts in hematological toxicity in induction, but that HiDAC was associated with a greater incidence of gastro-intestinal toxicities. There was no difference in induction mortality between the three cohorts, which was 11% overall. Consolidation with HiDAC led to a significant increase in hematological toxicity. Overall, the complete remission (CR) rate was 80% with no significant difference between the three regimens. The estimated disease free survival at 3 years was 28%, 67% and 54% respectively for Cohorts 1, 2 and 3 with an estimated overall survival of 38%, 63% and 47%. We conclude that cytarabine dosage can be escalated safely in combination with idarubicin and etoposide in both induction and consolidation. The combination is effective for induction treatment of AML and its side-effects appear similar to those of standard regimens. Whether its use offers long-term benefits compared with standard regimens is the subject of ongoing controlled randomized studies.

Adolescent↗
PubMed1999

Differential induction of nitric oxide synthase in rat gastric and vascular smooth muscle tissue: distinct tissue distribution and distinctive signaling pathways.

In rat aorta rings (RA) and in gastric circular muscle (CM) and gastric longitudinal muscle (LM) preparations maintained in vitro, inducible nitric oxide synthase (iNOS) induction was monitored functionally (1 mM L-arginine-induced relaxation), biochemically (appearance of iNOS mRNA), and immunohistochemically. Functional iNOS (L-arginine-mediated relaxation) was induced in RA and CM tissues (but NOT in the LM preparation) over 2 to 5 h. iNOS induction was detected by immunocytochemistry in RA smooth muscle elements and in macrophage-like cells in CM. Functional iNOS induction correlated with iNOS mRNA induction. In the RA and CM, functional iNOS induction was blocked by both actinomycin D and cycloheximide; actinomycin D also blocked the appearance of iNOS mRNA in both tissues. In contrast, cycloheximide blocked CM (but not RA) iNOS mRNA induction. In CM tissue, functional iNOS induction was not affected by genistein, tyrphostin 47/AG213, or vanadate. But, in the RA, both genistein and tyrphostin 47/AG213 blocked the appearance of functional iNOS; neither inhibitor prevented the appearance of RA iNOS mRNA. Vanadate, in the RA tissue, blocked both the appearance of iNOS mRNA and the induction of functional iNOS. In RA tissue, but not in the CM, inhibitors of NF-kappaB activation blocked the appearance of both functional iNOS and iNOS mRNA. We conclude that in different smooth muscle preparations (aorta versus gastric), there can be a differential induction of iNOS mRNA and "functional" iNOS not only in different cellular elements but also in terms of different signaling pathways.

Animals↗
PubMed1989

Induction of P-450IIB genes within the rat liver acinus is not dependent on the chemical inducer or on the acinar organization.

P-450IIB genes (P-450b and P-450e in rat) are induced following treatment with phenobarbital predominantly in hepatocytes located in zones 2 and 3 of the liver acinus. The previous finding of phenobarbital-mediated induction of P-450IIB mRNAs and apoproteins in the same zonal hepatocytes suggests that this differential induction is most likely due to zonal differences in the activation of gene transcription. To determine whether differential P-450IIB gene transcription was dependent on the type of inducer (i.e., inducer specificity) or on the capacity of hepatocytes located in different acinar zones to respond to inducers (i.e. zonal specificity), the pattern of acinar induction was evaluated following treatment with inducers that have diverse physiochemical properties and inductive capacities. The zonal distribution of P-450b and P-450e mRNAs in liver was determined by in situ hybridization after the administration of either phenobarbital, polychlorinated biphenyls, chlordane, or chlorpromazine. Liver sections were hybridized with 3H-labeled RNA transcripts of a P-450e cDNA that recognizes sequences of both P-450b and P-450e mRNAs and the pattern of zonal mRNA induction was measured by quantitative image analysis. Each inducer increased P-450b,e mRNA levels predominantly in hepatocytes of zones 2 and 3 of the hepatic acinus. The P-450b and P-450e apoproteins were induced in the same zonal hepatocytes as the P-450b,e mRNAs as shown by immunofluorescence studies using monoclonal antibodies. Therefore, differential transcriptional induction of the P-450IIB genes in the liver acinus does not seem to be dependent on a specific chemical inducer, but rather is a characteristic capacity of hepatocytes located in different acinar zones. To determine whether the induction of P-450b and P-450e was dependent on the liver tissue organization, hepatocytes were isolated by collagenase perfusion of the liver and transplanted into the spleens of syngeneic rats. Induction of P-450b and P-450e mRNAs and apoproteins, assessed 1 month after transplantation, was evident with each of the chemical inducers. These data suggest that, once hepatocytes have attained the capacity to respond to inducers, the organization of hepatocytes into acini and the sinusoidal microenvironment of the liver are not required for hepatocytes to maintain the ability to respond to inducers with an increase in transcription of P-450IIB genes. Moreover, the splenic hepatocytes demonstrated a heterogeneous pattern of P-450b,e apoprotein induction; this raises the possibility that the acinar organization is also not required for the heterogenous expression of P-450IIB genes.

Animals↗
PubMed1981

Induction of delta-aminolevulinate synthase and cytochrome P-450 hemoproteins in hepatocyte culture. Effect of glucose and hormones.

Addition of glucose to cultured chick embryo hepatocytes caused a concentration-dependent impairment of phenobarbital-mediated induction of delta-aminolevulinate (ALA) synthase resembling the "glucose effect" observed in rodents in vivo. This glucose effect occurred in the complete absence of extrahepatic factors such as serum and hormones. Fructose, glycerol, and lactate mimicked the inhibitory glucose effect on ALA synthase induction, whereas 2-deoxyglucose and 3-O-methylglucose augmented the induction evoked by phenobarbital. 2-Deoxyglucose reversed the effect of glucose, glycerol, and lactate on ALA synthase induction suggesting that the glucose effect is mediated by free glucose or glucose 6-phosphate or a nonglycolytic metabolite of glucose 6-phosphate. The phenobarbital-mediated induction of cytochrome P-450 hemoprotein(s) and its monooxygenase function were concomitantly diminished by glucose. However, this inhibitory effect or glucose was reversible by the addition of exogenous heme or ALA suggesting that the primary target of the glucose effect is ALA synthase induction and not synthesis of apocytochrome P-450. Glucagon and dibutyryl cAMP enhanced the induction of ALA synthase and cytochrome P-450 by phenobarbital and partially counteracted the glucose effect on both enzymes suggesting that the glucose effect may be mediated by changes in cAMP levels. Although insulin did not alter induction of ALA synthase, it impaired induction of cytochrome P-450 even in the presence of glucagon and cAMP. These data may be relevant for the treatment with glucose and heme of patients with "inducible" hepatic porphyria.

3-O-Methylglucose↗
PubMed2005

Anesthesia-assisted vs buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial.

CONTEXT: Rapid opioid detoxification with opioid antagonist induction using general anesthesia has emerged as an expensive, potentially dangerous, unproven approach to treat opioid dependence. OBJECTIVE: To determine how anesthesia-assisted detoxification with rapid antagonist induction for heroin dependence compared with 2 alternative detoxification and antagonist induction methods. DESIGN, SETTING, AND PATIENTS: A total of 106 treatment-seeking heroin-dependent patients, aged 21 through 50 years, were randomly assigned to 1 of 3 inpatient withdrawal treatments over 72 hours followed by 12 weeks of outpatient naltrexone maintenance with relapse prevention psychotherapy. This randomized trial was conducted between 2000 and 2003 at Columbia University Medical Center's Clinical Research Center. Outpatient treatment occurred at the Columbia University research service for substance use disorders. Patients were included if they had an American Society of Anesthesiologists physical status of I or II, were without major comorbid psychiatric illness, and were not dependent on other drugs or alcohol. INTERVENTIONS: Anesthesia-assisted rapid opioid detoxification with naltrexone induction, buprenorphine-assisted rapid opioid detoxification with naltrexone induction, and clonidine-assisted opioid detoxification with delayed naltrexone induction. MAIN OUTCOME MEASURES: Withdrawal severity scores on objective and subjective scales; proportions of patients receiving naltrexone, completing inpatient detoxification, and retained in treatment; proportion of opioid-positive urine specimens. RESULTS: Mean withdrawal severities were comparable across the 3 treatments. Compared with clonidine-assisted detoxification, the anesthesia- and buprenorphine-assisted detoxification interventions had significantly greater rates of naltrexone induction (94% anesthesia, 97% buprenorphine, and 21% clonidine), but the groups did not differ in rates of completion of inpatient detoxification. Treatment retention over 12 weeks was not significantly different among groups with 7 of 35 (20%) retained in the anesthesia-assisted group, 9 of 37 (24%) in the buprenorphine-assisted group, and 3 of 34 (9%) in the clonidine-assisted group. Induction with 50 mg of naltrexone significantly reduced the risk of dropping out (odds ratio, 0.28; 95% confidence interval, 0.15-0.51). There were no significant group differences in proportions of opioid-positive urine specimens. The anesthesia procedure was associated with 3 potentially life-threatening adverse events. CONCLUSION: These data do not support the use of general anesthesia for heroin detoxification and rapid opioid antagonist induction.

Adult↗
PubMed2005

Membrane sweeping for induction of labour.

BACKGROUND: Sweeping of the membranes, also named stripping of the membranes, is a relatively simple technique usually performed without admission to hospital. During vaginal examination, the clinician's finger is introduced into the cervical os. Then, the inferior pole of the membranes is detached from the lower uterine segment by a circular movement of the examining finger. This intervention has the potential to initiate labour by increasing local production of prostaglandins and, thus, reduce pregnancy duration or pre-empt formal induction of labour with either oxytocin, prostaglandins or amniotomy. 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 membrane sweeping for third trimester induction of labour. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (6 July 2004) and bibliographies of relevant papers. SELECTION CRITERIA: Clinical trials comparing membrane sweeping 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. 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. MAIN RESULTS: Twenty-two trials (2797 women) were included, 20 comparing sweeping of membranes with no treatment, three comparing sweeping with prostaglandins and one comparing sweeping with oxytocin (two studies reported more than one comparison). Risk of caesarean section was similar between groups (relative risk (RR) 0.90, 95% confidence interval (CI) 0.70 to 1.15). Sweeping of the membranes, performed as a general policy in women at term, was associated with reduced duration of pregnancy and reduced frequency of pregnancy continuing beyond 41 weeks (RR 0.59, 95% CI 0.46 to 0.74) and 42 weeks (RR 0.28, 95% CI 0.15 to 0.50). To avoid one formal induction of labour, sweeping of membranes must be performed in eight women (NNT = 8). There was no evidence of a difference in the risk of maternal or neonatal infection. Discomfort during vaginal examination and other adverse effects (bleeding, irregular contractions) were more frequently reported by women allocated to sweeping. Studies comparing sweeping with prostaglandin administration are of limited sample size and do not provide evidence of benefit. AUTHORS' CONCLUSIONS: Routine use of sweeping of membranes from 38 weeks of pregnancy onwards does not seem to produce clinically important benefits. When used as a means for induction of labour, the reduction in the use of more formal methods of induction needs to be balanced against women's discomfort and other adverse effects.

Extraembryonic Membranes↗
PubMed2001

Corticosteroids for 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. Some assumptions have been proposed regarding the mode of action of corticosteroids, including both a paracrine and autocrine action, following the identification of glucocorticoid receptors on human amnion. Given these studies it has been postulated that corticosteroids given intraamniotically will promote the induction of labour. 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: 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 corticosteroids 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: There are no included trials, hence no results are presented. REVIEWER'S CONCLUSIONS: The effectiveness of corticosteroids for induction of labour is uncertain. Use of this method of induction of labour is not commonly used and further research in this area is probably unwarranted.

Administration, Topical↗
PubMed2001

Oestrogens alone or with amniotomy for cervical ripening or induction of labour.

BACKGROUND: Studies in sheep showed that there is a pre-labour rise in oestrogen and a decrease in progesterone, both of these changes stimulate prostaglandin production and may help initiate labour. Though oestrogen has been suggested as an effective cervical ripening or induction agent, research in humans have failed to demonstrate a similar physiological mechanism. The use of oestrogen as an induction agent is not currently common practice, as such this systematic review should be regarded as an historical review. This is one of a series of reviews of methods of cervical ripening and labour induction using a standardised methodology. OBJECTIVES: To determine, from the best available evidence, the effectiveness and safety of oestrogens alone or with amniotomy for third trimester cervical ripening and induction of labour in comparison with other methods of 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: April 2001. SELECTION CRITERIA: (1) randomised controlled trials comparing oestrogens alone 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 generic strategy has been 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. The initial data extraction was done centrally. MAIN RESULTS: When comparing oestrogen with placebo there was no difference between the rate of caesarean section (7.1% versus 10.3%, relative risk (RR) 0.70, 95% confidence interval (CI) 0.30,1.62). There were no differences between rates of uterine hyperstimulation with or without fetal heart rate changes or instrumental vaginal delivery. None of the studies reported the rates of either vaginal delivery not achieved in 24 hours, or cervix unfavourable/unchanged after 12-24 hours. There were insufficient data to make any meaningful conclusions when comparing oestrogen with vaginal PGE2, intracervical PGE2, oxytocin alone or extra amniotic PGF2a, as to whether oestrogen is effective in inducing labour. REVIEWER'S CONCLUSIONS: There were insufficient data to draw any conclusions regarding the efficacy of oestrogen as an induction agent.

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