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PubMed1994

The induction of persistence of I-A expression by macrophages from Bcgr mice occurs via a protein kinase C-dependent pathway.

We have described conditions by which MHC class II (I-A) glycoproteins can be induced to be differentially expressed after treatment of macrophages with rIFN-gamma. Treatment of macrophages from BCG-resistant mice with 1 U of rIFN-gamma induced transient I-A expression that decayed in the presence of cycloheximide. Subsequent treatment of these macrophages with 100 U of rIFN-gamma induced the persistence of I-A that was not affected by cycloheximide. The aim of this investigation was to define, by pharmacologic intervention, the second signals that resulted in the induction of persistence of I-A. Treatment of the macrophages that transiently expressed I-A with PMA resulted in the induction of persistence. When we compared the effect of different protein kinase C (PKC) inhibitors with the induction of persistence by rIFN-gamma, we found that H-7 blocked the induction of persistence only when added before or at the same time as the addition of a high dose of rIFN-gamma. In contrast, the addition of staurosporine to macrophages as late as 2 h after treatment with high doses of rIFN-gamma inhibited the induction of I-A persistence. The addition of a high dose of rIFN-gamma to macrophages previously treated with a low dose of rIFN-gamma resulted in the synergistic activation of PKC. The effect of H-7 and of staurosporine on the activation of PKC activity coincided with the effect of these inhibitors on the induction of persistent I-A expression. Tyrosine kinase inhibitors genistein and herbimycin did not affect the induction of I-A persistence nor of PKC activation. Antibody to the IFN-gamma receptor inhibited PKC activation. Finally, the addition of the high dose of rIFN-gamma to macrophages from BALB/c.Bcgs mice, previously treated with the low dose of rIFN-gamma, failed to activate high levels of PKC activity attained after similar treatment of macrophages from BALB/c.Bcgr mice. One effect of the Bcg gene may be to regulate the activation of PKC activity.

Animals↗
PubMed1993

[ST segment changes in the ECG. Anesthesia induction with propofol, etomidate or midazolam in patients with coronary heart disease].

Induction of anaesthesia with propofol and fentanyl can lead to marked reductions in mean arterial pressure (MAP) and heart rate (HR). Thus, the application of propofol in patients with severely reduced coronary artery perfusion is controversial. METHODS. The study group consisted of 60 patients undergoing coronary artery bypass grafting (CABG). Anaesthesia was induced over 30 s with propofol (P 1.5 mg/kg), etomidate (E 0.3 mg/kg), or midazolam (M 0.15 mg/kg) following a bolus dose of fentanyl (5 micrograms/kg). Vecuronium was used as a muscle relaxant. During induction we continuously measured MAP and HR and recorded the occurrence of myocardial ischaemia using an automatic ST-segment analyser (Marquette 7010). ST-segment deviations of more than 1 mm in leads II and V5 were interpreted as significant signs of myocardial ischaemia. RESULTS. All groups showed reductions in MAP and HR on induction that were marked in the P group. Intubation caused elevation of MAP and HR to pre-induction levels (HR: all groups) or slightly above (MAP: E, M). Four patients in the P group and 3 in each other group showed significant ST-segment deviation prior to induction. In the P group these deviations disappeared in 2 patients after injection while they remained unchanged in the M group. In the E group injection had no effect on the ischaemic ECG changes but produced another case of significant ST-segment deviation. Laryngoscopy and intubation produced no further significant ST-segment deviation in either group. DISCUSSION. Induction is a critical phase of anaesthesia, especially in patients with limited coronary reserve. Induction agents should alleviate the stress response while causing minimal haemodynamic changes. Despite marked reductions in MAP in the P group, the number of patients with ischaemic ECG changes was cut by half. Their number was unchanged or even raised in the other groups. After application of P, with an alleged reduction of coronary perfusion, a compensational reduction in myocardial oxygen consumption may occur.

Aged↗
PubMed1993

[Quality of induction and adrenocortical function. A clinical comparison of Etomidate-Lipuro and Hypnomidate].

UNLABELLED: The purpose of this study was to compare etomidate in a lipid emulsion (Etomidat-Lipuro; Braun, Melsungen) and in propylene glycol (Hypnomidate, Janssen Pharmaceutica) in 90 patients in terms of anaesthetic induction characteristics with special reference to injection side effects, haemodynamic changes, and quality of induction. Adrenocortical hormones were determined in 30 patients who received either Etomidat-Lipuro, Hypnomidate, or propofol (Diprivan, ICI Pharma) for induction of anaesthesia. METHODS: One hundred twenty patients gave their informed consent to the study. In the first part, 90 patients were assigned at random to two groups in which induction of anaesthesia was performed either with Etomidat-Lipuro or Hypnomidate. Anaesthesia was started by i.v. injection of 25 micrograms/kg alfentanil (Rapifen, Janssen Pharmaceutica). One minute later, the hypnotic agent was injected into a freely running i.v. line (18 Gcannula) that was used only for the hypnotic and was removed 15 min later. During injection, the patients were asked to inform the anaesthesiologist spontaneously and on request about their sensations at the injection site. The time from the beginning of anaesthesia until the disappearance of the eyelash reflex was measured. The patients were ventilated and vecuronium was administered to allow good intubation conditions 2-3 min later. For the first 10 min, blood pressure and heart rate were measured every minute. Postoperatively, the same investigator made rounds once a day and examined the injection sites. Signs of pain, redness, swelling, induration, thrombophlebitis, or thrombosis were noted. In the second part of the study, 30 patients were investigated for endocrinological changes after induction of anaesthesia with Etomidat-Lipuro, Hypnomidate, or Diprivan. The patients were allocated to the groups at random. A radial artery catheter was inserted in every patient. Sampling took place 30 min before and 1 and 2 h after induction. Additional samples were drawn 30 min and 1, 2, and 22 h after i.v. administration of 0.25 mg ACTH (Synacthen, Ciba-Geigy). The plasma concentrations of cortisol, 17 alpha-OH-progesterone, and aldosterone and the renin activity were determined by high-performance liquid chromatography. RESULTS: The loss of the eyelash reflex occurred 42.9 +/- 8.7 and 42.2 +/- 11.0 s after the administration of Etomidat-Lipuro and Hypnomidate. The haemodynamic changes were minimal in both groups. After administration of alfentanil, local side effects of the hypnotics were scarce, with a tendency to be weaker and more seldom after Etomidat-Lipuro (3/55 versus 8/55). The postoperative vein reactions were generally mild and occurred in 17 out of 55 patients after Etomidat-Lipuro and 15 out of 55 patients after Hypnomidate. In most cases these signs were no longer present on the 2nd day after the procedure. Cortisol levels were depressed initially by all the hypnotic drugs used. While there was spontaneous recovery in the Diprivan group after 2 h combined with a positive overshooting response to ACTH stimulation, in the etomidate groups cortisol could not be stimulated; it normalized slowly during the following 24 h. The 17 alpha-OH-progesterone increase was significant in the etomidate groups after the administration of ACTH. The aldosterone levels decreased after etomidate injection and had not normalized 24 h later, while there was a normal response to ACTH in the propofol group. There was a normal decrease in renin activity in all three groups after the administration of ACTH. CONCLUSION: Local side effects are minimal after the administration of Etomidat-Lipuro and Hypnomidate. Alfentanil reduces the injection pain of etomidate induction agents. Cortisol and aldosterone are depressed by etomidate, but the clinical relevance is minimal after a single bolus injection.

Adolescent↗
PubMed1993

Induction of labour with prostaglandin E2; a prospective audit.

AIMS: To perform a prospective audit of inductions of labour using prostaglandins to assess the protocols for induction in use at that time. METHODS: Data on 123 patients was obtained over a six-week period. Information regarding gestation, indication for induction and relevant details of labour and delivery were obtained. RESULTS: There were three (2.5%) patients with hyperstimulation and six (5%) with failed induction. Nulliparous patients with an unfavourable cervix had an increased caesarean section rate (29%) and a prolonged induction to delivery interval (mean: 27 hours). CONCLUSIONS: The protocols for induction of labour using prostaglandins presently in use appear to be safe although staff need to be well informed about the management of hyperstimulation should it occur. Further audit of indications for induction of labour and of the caesarean section rate is required.

Dinoprostone↗
PubMed1995

Nitric oxide mediated metallothionein induction by lipopolysaccharide.

The roles of calcium and/or of the other cellular transduction pathways, and of nitric oxide (NO) on the induction of metallothionein (MT) mRNA by lipopolysaccharide (LPS) has been studied in rat primary cell culture, using inhibitors of protein kinase pathways (H-7, W-7 and TMB-8) and NO production inhibitors (L-NAME, PTIO). LPS exposure led to a rapid increase of MT-mRNA and a peak level revealed 2.5-fold induction as compared to control for 6h incubation at a dose of 3.0 mg/L. A dose of 5.0 and 10.0 mg/L of LPS also provided the same level of MT-mRNA induction. The inhibition of MT induction by LPS was observed with L-NAME, PTIO, but not H-7, W-7. These findings indicate that the alteration of cellular calcium concentration and distribution does not relate to the induction of MT-mRNA by LPS in hepatocytes and that protein kinase C and calmodulin dependent protein kinase pathways have not contributed to MT-mRNA induction by LPS. Finally, the present results show that NO plays an important role in MT induction by LPS.

Animals↗
PubMed1996

Stem cell factor enhances interleukin-3 dependent induction of 68-kD calmodulin-binding protein and thymidine kinase activity in NFS-60 cells.

Stem cell factor (SCF) is known to act synergistically with other hematopoietic factors in increasing the colony formation of hematopoietic progenitor cells. We have shown that interleukin-3 (IL-3)-dependent proliferation of NFS-60 cells is associated with the induction of a specific calmodulin-binding protein of about 68 kD (CaM-BP68). To evaluate the relationship between proliferative stimulation and the induction of CaM-BP68 by cytokines, we examined whether the increased proliferative potential of NFS-60 cells in response to SCF is reflected in an increased induction of the CaM-BP68. We observed that SCF alone has a limited effect on proliferative stimulation and on the induction of CaM-BP68 in factor-deprived NFS-60 cells. However, when combined with IL-3, granulocyte colony-stimulating factor (G-CSF), or IL-6, it caused a significant increase in cytokine-dependent proliferative stimulation, as well as in the induction of CaM-BP68. Furthermore, an increase in IL-3-dependent induction of CaM-BP68 in the presence of SCF coincided with a corresponding increase in thymidine kinase activity, whose expression is linked to G1/S transition of the cells. At low concentrations SCF caused a synergistic increase in IL-3-dependent induction of both CaM-BP68 and thymidine kinase activity. In contrast to the changes in CaM-BP68 and thymidine kinase activity, no significant changes in DNA polymerase alpha were observed in factor-deprived NFS-60 cells in response to IL-3 and/or SCF. These observations suggest an increased expression of CaM-BP68 and thymidine kinase are associated with the synergistic effect of SCF on factor-dependent proliferation of hematopoietic progenitor cells.

Animals↗
PubMed1995

Co-induction of anaesthesia: day-case surgery.

The term co-induction of anaesthesia has been applied to the use of two or more drugs to induce anaesthesia. The term was introduced in 1986 to describe the unplanned induction of anaesthesia by non-anaesthetically trained personnel practising sedation. A new benzodiazepine was combined with opioids, with synergistic effects, causing unplanned anaesthesia in an unsuitable environment leading to several fatalities. Currently, planned co-induction of anaesthesia is practised by anaesthetists exploiting drug interactions, particularly synergism, principally between midazolam, fentanyl, sufentanil and alfentanil, and propofol. It can produce an improvement in all phases of anaesthesia, including induction, maintenance and recovery. There are advantages in combining midazolam with propofol, thereby reducing the risk of awareness and also the dose of propofol and hence its side-effects and cost. Propofol is the principal intravenous induction agent for day-case anaesthesia. The pre-administration of 0.03 mg kg-1 of midazolam (approximately 2 mg in normal healthy adults) is now being practised widely. Current papers suggest that 2 mg of midazolam administered to an average, otherwise healthy, adult does not compromise recovery, whereas an increase to 5 mg may be expected to delay the possibility of final discharge of such patients by about 20 min. The use of midazolam and propofol with or without either fentanyl or alfentanil is probably the principal technique for the induction of day-case anaesthesia at the present time. A major advantage is that by reducing the dose of propofol there is less chance of the severe bradycardia that is sometimes associated with the combined use of propofol and opioids, although this can be prevented by vagolytic agents. However, the use of opioids increases the incidence of post-operative nausea and vomiting. Another important drug is ketamine, the effects of which are often additive with other drugs. The combination of ketamine and midazolam is an important technique, particularly in the management of critically ill patients. The alpha 2-agonists, e.g. clonidine and dexmedetomidine, may also have a role in this context in the future. This paper presents the current approach to the co-induction of anaesthesia, particularly in relation to the reduced risk of awareness when using midazolam, and the health economics in relation to the potential reduction in the dose and hence cost of propofol.

Adult↗
PubMed1996

Induction of hippocampal long-term depression requires release of Ca2+ from separate presynaptic and postsynaptic intracellular stores.

Studies have suggested that an increase in intracellular [Ca2+] is necessary for the induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission, and that release of Ca2+ from intracellular storage pools can be necessary to induce LTP. We investigated whether release of Ca2+ from intracellular stores also is required for the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Both thapsigargin (1 microM) and cyclopiazonic acid (1 microM), compounds that deplete all intracellular Ca2+ pools by blocking LTP-dependent Ca2+ uptake into intracellular compartments, blocked the induction, but not maintenance, of LTD by low-frequency stimulation (LFS) (1 Hz/15 min) without affecting baseline synaptic transmission. Washout of the reversible inhibitor cyclopiazonic acid restored the ability to induce LTD. In contrast, thapsigargin did not block depotentiation of LTP by 1 Hz LFS, suggesting that LTP causes a reduction in the threshold [Ca2+] necessary for LTD. Selective depletion of the ryanodine receptor-gated Ca2+ pool by bath application of ryanodine (10 microM) also blocked the induction of LTD, indicating a requirement for Ca(2+)-induced Ca2+ release. Impalement of CA1 pyramidal neurons with microelectrodes containing thapsigargin (500 nM to 200 microM) prevented the induction of LTD at synapses on that neuron without blocking LTD in the rest of the slice. In contrast, similar filling of CA1 pyramidal neurons with ryanodine (2 microM to 5 mM) did not block the induction of LTD. From these data, we conclude that the induction of LTD requires release of Ca2+ both from a presynaptic ryanodine-sensitive pool and from postsynaptic (presumably IP3-gated) stores.

Animals↗
PubMed1995

Induction of labour with intravaginal misoprostol in the second and third trimesters of pregnancy.

OBJECTIVE: To confirm the effectiveness of misoprostol as a labour-induction agent. DESIGN AND SETTING: One hundred and ten consecutive second- and third-trimester hospital patients. Patients with intra-uterine deaths (group A) received 100 micrograms misoprostol 4-hourly and those with live fetuses (group B) 50 micrograms misoprostol 4-hourly until labour commenced. SUBJECTS: Forty-eight patients in group A (group A1 second trimester 27, group A2 third trimester 21); 62 mainly hypertensive patients in group B. OUTCOME MEASURES: These were the amount of misoprostol required to induce labour; duration of induction and labour; success and completeness of vaginal delivery; neonatal outcome; and cost. RESULTS: In group A1, labour was successfully induced in 21/27 (77.8%) patients with 157.4 micrograms misoprostol; and in 19/21 (90.5%) patients in group A2 with 128.9 micrograms misoprostol. Cost per successful induction was R0.55 and R0.44 respectively. Mean induction times were 13.2 hours and 13.4 hours respectively. All patients delivered vaginally but incompletely in 7/21 group A1 and 1/19 group A2 patients. In group A2, the mean duration of labour was 5.97 hours. In group B induction was successful in 51/62 (82%) with 95.1 micrograms of misoprostol; the mean cost was R0,32. Twelve out of 51 (23%) received oxytocin and 44/51 delivered vaginally. Mean duration of induction was 11.4 hours and of labour 5.4 hours. Two babies had low Apgar scores. There were two stillbirths (perinatal mortality rate 39.2/1000), both apparently unrelated to misoprostol. CONCLUSIONS: Misoprostol is an effective, easy to use, apparently safe and cheap drug for the induction of labour.

Administration, Intravaginal↗
PubMed1996

[Rapid induction of anesthesia with propofol--comparison with thiopental].

We investigated hemodynamic changes, induction time and the incidence of pain after rapid induction of anesthesia with propofol (Group P) in comparison with those after induction with thiopental (Group B). Anesthesia was induced with propofol 2.5 mg.kg-1 in Group P and thiopental 5 mg.kg-1 in Group B taking 20 seconds. When verbal response disappeared, tracheal intubation was performed with suxamethonium 1.2 mg.kg-1. The incidence of pain on injection, time from the start of injection of the drug to the disappearance of verbal response (induction time), blood pressure, heart rate, and rate pressure product (RPP) were monitored. The pain on injection was seen in 6 of 30 patients in Group P. This was significantly larger compared with 3 patients in Group B. The induction time was not different between the two groups. One minute after intubation, blood pressure, heart rate and RPP were significantly higher compared with those before induction in Group B. These were also significantly higher than those in Group P. Therefore, rapid induction with propofol is more useful compared with that with thiopental.

Adult↗
PubMed1998

Use of the urine cortisol-to-creatinine ratio for monitoring dogs with pituitary-dependent hyperadrenocorticism during induction treatment with mitotane (o,p'-DDD).

OBJECTIVE: To determine whether the urine cortisol-to-creatinine ratio (UCCR) could replace the ACTH stimulation test in monitoring effectiveness of mitotane induction treatment in dogs with pituitary-dependent hyperadrenocorticism (PDH). ANIMALS: 15 dogs with PDH. PROCEDURE: All 15 dogs were given an induction dose of mitotane (o,p'-DDD: 35 to 50 mg/kg of body weight/d) for 3 to 14 days. During the induction period, free-catch morning urine samples were collected for determination of UCCR, followed by ACTH stimulation testing, every other day. Treatment response was divided into 3 categories: well-controlled PDH (post-ACTH serum cortisol concentration > or = 28 nmol/L but < or = 138 nmol/L), deficient cortisol secretion (post-ACTH serum cortisol concentration < 28 nmol/L), and excess cortisol secretion (post-ACTH serum cortisol concentration > 138 nmol/L). RESULTS: The linear relation between UCCR and post-ACTH serum cortisol concentration was significant (P < 0.001); however, the prediction intervals surrounding the line were too broad to be clinically useful. The UCCR overlapped among the 3 categories of treatment response. Nevertheless, dogs with PDH receiving mitotane induction treatment and with UCCR > 79 x 10(-6) were always classified as having excess cortisol secretion. CONCLUSION AND CLINICAL RELEVANCE: The UCCR failed to predict post-ACTH cortisol concentration during mitotane induction treatment sufficiently close to be a clinically reliable indicator of treatment control. Seemingly, however, UCCR > 79 x 10(-6) obtained from a dog with PDH during mitotane induction would indicate inadequate adrenal cortex destruction and the need for continued mitotane induction; UCCR < or = 79 x 10(-6) would be inconclusive.

Adrenocortical Hyperfunction↗
PubMed1998

[Comparative study of sevoflurane and nitrous oxide versus halothane and nitrous oxide in pediatric anesthesia: efficacy and hemodynamic characteristics during induction].

OBJECTIVES: To study the efficacy, side effects and hemodynamics of anesthetic induction in pediatric patients using sevoflurane and nitrous oxide or halothane and nitrous oxide. PATIENTS AND METHODS: We studied 80 pediatric ASA I-II patients aged between 1 and 10 years old scheduled for infraumbilical surgery of short duration. The patients were randomly assigned to two groups of 40 to receive one of the two drug combinations. All the children were premedicated with nasal midazolam 0.2 mg.kg-1. Induction was by inhalation of increasing concentrations of sevoflurane or halothane. The maximum inspired concentration during induction was 7% for sevoflurane and 3% for halothane. We analyzed induction time, side effects and hemodynamic variables. RESULTS: The induction time was 2.06 +/- 0.5 min for halothane and 1.6 +/- 0.6 min for sevoflurane (p < 0.01). We observed no differences between the groups in coughing, laryngospasm, bronchospasm, secretions, apnea, nausea, vomiting, agitation or hiccoughing. Supraventricular beats appeared in 22.5% of patients in the halothane group and in 5% of the sevoflurane group. Induction with both anesthetics caused significant decreases from baseline blood pressure levels but no significant changes in heart rate. CONCLUSIONS: Inhaled sevoflurane in 60% nitrous oxide provides rapid but gentle anesthetic induction, with hemodynamic stability and a low incidence of airway complications. Sevoflurane is therefore a reasonable alternative to halothane for pediatric surgery.

Anesthesia, Inhalation↗
PubMed1998

Effect of N-acetylcysteine on heat shock protein induction by acetaminophen in mouse liver.

It was previously shown that a necrogenic dose of acetaminophen (APAP) induced the 25- and 70-kDa heat shock proteins (hsp25 and hsp70i) in mouse liver, whereas nonnecrogenic doses failed to alter the level of either hsp. A strong correlation between the intralobular sites of APAP arylation of protein and hsp induction suggested that APAP-induced protein denaturation may play a role in triggering hsp induction. This study was conducted to determine whether APAP arylation of protein without concurrent toxicity could cause hsp induction. APAP (250 mg/kg i.p.) hepatotoxicity was eliminated using N-acetylcysteine (NAC, 300 mg/kg i.p.) or the cytochrome P-450 inhibitor diallyl sulfide (200 mg/kg p.o.). NAC did not inhibit APAP arylation of protein when administered 1 or 3 hr after the APAP dose but decreased binding by approximately 50% when administered at the same time as the APAP dose. Even though APAP hepatotoxicity was blocked by NAC administered 0 or 1 hr after the APAP dose, NAC did not inhibit the induction of hsp25 or hsp70i, indicating that APAP arylation of protein may play a key role in triggering hsp induction. Diallyl sulfide blocked APAP arylation of protein, hepatotoxicity, and induction of both hsps. These data are consistent with the hypothesis that toxicant adduction of protein triggers hsp induction.

Acetaminophen↗
PubMed1998

DNA photodamage, repair, gene induction and genotoxicity following exposures to 254 nm UV and 8-methoxypsoralen plus UVA in a eukaryotic cell system.

The induction and repair of different types of photodamage and photogenotoxicity in eukaryotic cells have been the subject of many studies. Little is known about possible links between these phenomena and the induction of DNA damage-inducible genes. We explored this relationship using the yeast Saccharomyces cerevisiae, a pertinent eukaryotic model. Previous results showed that the photogenotoxic potential of 8-methoxypsoralen (8-MOP) plus UVA is higher than that of UV (254 nm). Moreover, the induction of the ribonucleotide reductase gene RNR2 by UV and 8-MOP plus UVA in an RNR2-LACZ fusion strain and the formation of DNA double-strand breaks (dsb) as repair intermediates after such treatments suggest that the latter process could involve a signal for gene induction. To further substantiate this, we measured the induction of the DNA repair gene RAD51 in RAD51-LACZ fusion strains using the dsb repair and recombination deficient mutant rad52 and the corresponding wild type, and we determined the formation of dsb by pulsed-field gel electrophoresis. After treatments, the resealing of dsb formed as repair intermediates was impaired in the rad52 mutant. At equal doses, i.e. the same number of lesions, the induction of the RAD51 gene by UV or 8-MOP plus UVA was significantly reduced in the rad52 mutant as compared with the wild type. The same was true when equitoxic doses were used. Thus, the RAD52 repair pathway appears to play an important role not only in dsb repair but also in gene induction. Furthermore, the signaling pathways initiated by DNA damage and its processing are somewhat linked to the photogenotoxic response.

Cell Division↗
PubMed1998

CBFbeta-SMMHC, expressed in M4eo acute myeloid leukemia, reduces p53 induction and slows apoptosis in hematopoietic cells exposed to DNA-damaging agents.

CBFbeta-SMMHC is expressed in M4Eo acute myeloid leukemia (AML) as a result of inv(16), but how it contributes to leukemogenesis is unknown. p53 mutations are rare in de novo AML, but they are common in many malignancies. Expression of CBFbeta-SMMHC in Ba/F3 cells reduced p53 induction in response to ionizing radiation or etoposide 3- to 4-fold. However, p53 induction was normal in Ba/F3 cells expressing a CBFbeta-SMMHC variant that does not interfere with DNA binding by CBF, indicating that a CBF genetic target regulates p53 induction. The p53 gene may be regulated by CBF, because p53 mRNA levels were reduced by CBFbeta-SMMHC. Reduced p53 induction was not caused by slowed cell proliferation, a consequence of CBFbeta-SMMHC expression, because p53 was induced similarly in control cultures and in cultures propagated in 10-fold less interleukin-3 (IL-3). CBFbeta-SMMHC did not slow apoptosis resulting from IL-3 withdrawal, where p53 induction is minimal, but slowed apoptosis in Ba/F3 cells exposed to 10 Gy of ionizing radiation or 3 to 8 microgram/mL etoposide, providing 2-fold protection at 6 or 18 hours. Inhibition of apoptosis was temporary, because all the cells exposed to these doses ultimately died, and clonal survival assays performed using 0. 04 microgram/mL etoposide did not show protection by CBFbeta-SMMHC. p21 levels were increased in cells subjected to DNA damage, regardless of CBFbeta-SMMHC expression and attenuated p53 induction. Bcl-2, bcl-xL, bcl-xS, and bax levels were unaffected by CBFbeta-SMMHC. Attenuated p53 induction may contribute to leukemogenesis by CBFbeta-SMMHC by slowing apoptosis via a p21-independent mechanism.

Acute Disease↗
PubMed1999

Insulin-mediated modulation of cytochrome P450 gene induction profiles in primary rat hepatocyte cultures.

In this investigation, we examined the effects of insulin on gene induction responsiveness in primary rat hepatocytes. Cells were cultured for 72 hours either in the absence or presence of 1 microM insulin and then exposed to increasing concentrations of phenobarbital (PB; 0.01-3.5 mM). Culturing in the absence of insulin produced 1.5-2-fold increases in the induction magnitude of CYP2B1 and CYP2B2 mRNA expression resulting from PB exposures, without altering the bell-shaped dose-response curve characteristic of this agent. However, for the CYP3A1 gene, insulin removal led to a pronounced shift in both the PB-induction magnitude and dose-response relationships of the induction response, with higher levels of CYP3A1 expression resulting from exposures to lower concentrations of inducer. Insulin removal also reduced the time required to attain maximal induction of CYP2B1/2 and CYP3A1 gene expression. The insulin effects were not specific for PB induction, as insulin deprivation similarly enhanced both dexamethasone- and beta-naphthoflavone-inducible CYP3A1 and CYP1A1 expression profiles, respectively. In contrast, the level of albumin mRNA expression was reduced considerably in cells deprived of insulin. We conclude that insulin is an important regulator of inducible and liver-specific gene expression in primary rat hepatocytes.

Animals↗
PubMed1990

Teniposide (VM-26) and continuous infusion cytosine arabinoside for initial induction failure in childhood acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study.

Twenty-six evaluable children with newly diagnosed acute lymphoblastic leukemia (ALL) who failed to achieve initial remission after receiving two to seven drugs for at least a 4-week period were given teniposide (VM-26) and continuous infusion cytosine arabinoside (Ara-C). Twenty-two received 150 mg/m2 of VM-26 on days 1 and 2 with 100 mg/2 of Ara-C as a continuous infusion on days 1 through 5; a second shortened course was given on day 14 to eight patients who had evidence of some antileukemic effect or were clinically judged able to tolerate a second course. The last four patients received three daily doses of VM-26 and a 7-day infusion of Ara-C at the same daily dosages. Twelve (48%) achieved complete remission (CR) of ALL. There was a trend toward decreasing response rates with an increasing number of drugs used in the initial induction regimen, i.e., five CR among seven patients with a prior two-drug induction attempt, six CR among 14 patients with a prior three- to four-drug induction attempt, and one CR among four patients with a prior five- to seven-drug induction attempt (P = 0.14). Ten of 17 non-T-cell patients and two of nine T-cell patients achieved remission (P = 0.10). The median time required to achieve a complete remission from the initiation of treatment was 26 days (range, 14-72 days). This period was shorter in those who required one course compared with those who required two induction courses, i.e., 25 days median vs. 44 days median. Toxicity was significant and due mainly to marrow aplasia and infection; one patient had severe prolonged VM-26-induced hypotension. Of the 12 patients entering remission, two were removed for marrow transplant and one was removed due to parental request. In the remaining nine patients, median remission duration was only 2 months (range, 1-18 months). All nine patients relapsed in the marrow. Among the entire group of 26 patients, only one patient is alive and a long-term event-free survivor (after allogeneic marrow transplant). Due to the current use of more aggressive initial induction regimens and the extremely poor prognosis in children who fail to achieve initial remission, more intensive regimens of continuation therapy or alternative therapies, such as bone marrow transplant, should be considered.

Adolescent↗
PubMed2003

Methotrexate for induction of remission in refractory Crohn's disease.

BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, approximately 20% of patients who respond relapse when steroids are withdrawn and become steroid dependent (Binder 1985). Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine/6MP therapy. The evidence for its effectiveness has not been subjected to a systematic review. OBJECTIVES: To conduct a systematic review of the evidence for effectiveness of methotrexate for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. SEARCH STRATEGY: A computer-assisted search of MEDLINE and EMBASE for relevant studies published in English, French, Spanish, Italian and German between 1966 and June 2002. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. The Cochrane Controlled Trials Register and the IBD Review Group Specialized Trials Register were also searched. SELECTION CRITERIA: Randomized controlled trials involving patients of age > 17 years with refractory Crohn's disease defined by conventional clinical, radiological and endoscopic criteria, which was categorized as being active (Crohn's disease activity index >150). DATA COLLECTION AND ANALYSIS OUTCOME MEASURES: The outcome measure was the rate of induction of remission and complete withdrawal from steroids in the treatment and control groups after 16 weeks of treatment. A secondary outcome was induction of remission with reduction in steroid dose of at least 50%. Selection of trials: The results of the searches above were reviewed independently by two observers and relevant studies selected according to the predefined selection criteria. Any disagreement among reviewers was resolved by consensus. The same two reviewers assessed the methodological quality of each trial (details of randomization method, including whether intention-to-treat analysis was possible from the published data, number of patients lost to follow-up, and if a blinded outcome assessment was used). A standard data extraction form was used. Appropriateness of combining results: Trials were first reviewed to assess the clinical comparability of trial protocols and study populations. MAIN RESULTS: Three randomized placebo-controlled trials were identified. The three studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to combine the data statistically. Two studies which employed low doses of methotrexate orally showed no statistically significant difference between methotrexate and placebo treated patients, and one which employed a higher dose intramuscularly showed substantial benefit (number needed to treat, NNT=5). Adverse effects were more common with high dose intramuscular methotrexate therapy than with placebo. REVIEWER'S CONCLUSIONS: There is evidence from a single large randomized trial on which to recommend the use of methotrexate 25 mg intramuscularly weekly for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Although adverse effects are more common than with placebo, they were not severe. There is no evidence on which to base a recommendation for use of lower dose oral methotrexate.

Crohn Disease↗