Blood levels of propofol during induction of anesthesia.
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Aged↗
Biomedical subjects
A Bartoli
Publications and source records attributed to A Bartoli.
Identification of three novel mRNA splice variants of GITR.
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Alternative Splicing↗
Gene structure and chromosomal assignment of mouse GITR, a member of the tumor necrosis factor/nerve growth factor receptor family.
GITR is a type I transmembrane protein that belongs to the tumor necrosis factor/nerve growth factor receptor (TNF/NGFR) family. This receptor is preferentially expressed in activated T lymphocytes and may function as signaling molecule during T-cell development. In the present study, we examined the genomic organization of the entire mouse GITR (mGITR) gene. The gene spans a 2543-bp region and consists of five exons (with a length ranging from 88 bp to 395 bp) and four introns (67 bp to 778 bp). In agreement with GITR expression in activated T cells, consensus elements for transcription factors involved in T-cell development and activation were identified in the 5' flanking region, including a consensus element for NF-kappaB. Two highly significant binding sites for MyoD and one binding site for myogenin were also found, suggesting involvement of GITR in muscle development. The mGITR gene contains 17 transcription initiation sites distributed over a 76-bp region, all used with the same frequency. We localized mGITR to the murine chromosome 4 (E region), where other 4 TNF/NGFR members localize, including m4-1BB and mOX40. These results further indicate that GITR shares several features with OX40, 4-1BB, and CD27, suggesting the existence of a new subfamily of the TNFR family, as also confirmed by the similarity of their cytoplasmic domains.
Amino Acid Sequence↗
A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy.
PURPOSE: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy. METHODS: One-hundred eighty patients with partial or idiopathic generalized nonabsence epilepsy, aged 6 to 65 years, requiring initiation of treatment with carbamazepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbital (PB), or primidone (PRM) were randomly allocated to two groups according to an open, prospective parallel-group design. In one group, dosage was adjusted to achieve serum AED concentration within a target range (10-20 microg/ml for PHT, 15-40 microg/ml for PB, 4-11 microg/ml for CBZ, and 40-100 microg/ml for VPA), whereas in the other group, dosage was adjusted on clinical grounds. Patients were followed up for 24 months or until a change in therapeutic strategy was clinically indicated. RESULTS: Baseline characteristics did not differ between the two groups. Most patients with partial epilepsy were treated with CBZ, whereas generalized epilepsies were most commonly managed with PB or VPA. PHT was used only in a small minority of patients. A total of 116 patients completed 2-year follow-up, and there were no differences in exit rate from any cause between the monitored group and the control group. The proportion of assessable patients with mean serum drug levels outside the target range (mostly below range) during the first 6 months of the study was 8% in the monitored group compared with 25% in the control group (p < 0.01). There were no significant differences between the monitored group and the control group with respect to patients achieving 12-month remission (60% vs. 61%), patients remaining seizure free since initiation of treatment (38% vs. 41%), and time to first seizure or 12-month remission. Frequency of adverse effects was almost identical in the two groups. CONCLUSIONS: Only a small minority of patients were treated with PHT, the drug for which serum concentration measurements are most likely to be useful. With the AEDs most commonly used in this study, early implementation of serum AED level monitoring did not improve overall therapeutic outcome. and the majority of patients could be satisfactorily treated by adjusting dose on clinical grounds. Monitoring the serum levels of these drugs in selected patients and in special situations is likely to be more rewarding than routine measurements in a large clinic population.
Adolescent↗
Effects of subinhibitory concentrations of moxifloxacin in an in-vitro dynamic model.
The postantibiotic effect (PAE), sub-MIC effect (SME) and postantibiotic sub-MIC effect (PASME) of moxifloxacin were investigated in an in-vitro dynamic model reproducing in-vivo elimination kinetics of the antibiotic. The PAE was induced by exposing strains of Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli and Klebsiella pneumoniae to 5 x MIC of the antibiotic for 1.5 hours. After induction, cultures were washed to eliminate the antibiotic and resuspended into the dynamic model either in the presence or absence of a subinhibitory concentration of the antibacterial agent of 0.5 x MIC. Unexposed controls were treated similarly. PASMEs were constantly longer than corresponding SMEs, but differences between them were not statistically significant. Both PASMEs (mean 11:17 hours, range from 8:17 to 14:57) and SMEs (mean 9:23 hours, range from 6:03 to 12:34) had an initial bactericidal effect and were significantly longer than PAEs (mean 1:31 hours, range from 0:21 to 2:14). The primary effect of moxifloxacin sub-MICs appears to be prevalent in PAE. The possibility of once-daily dosing of the drug is strengthened.
Anti-Infective Agents↗
Effect of interleukin-2 on generation of natural killer cells: role of major histocompatibility complex class I in B6 and TAP-1-/- mice.
Long-term bone marrow cultures were used to investigate the effect of IL-2, a cytokine widely used in immunotherapy, on natural killer cell differentiation. Specifically, the role of MHC was evaluated by comparing normal B6 and class I-deficient TAP-1-/- mice. The number of cells generated after a 13-day culture was the same in cell cultures from TAP-1-/- or B6 mice but the relative number of natural killer cells, identified as NK-1.1+CD3- cells by flow cytometry analysis, was increased in TAP-1-/- compared to B6 cultures (74.4% and 63.9%, respectively). Addition of an anti-class I mAb determined a strong inhibition of natural killer cell generation in B6 cultures, and its effect was specific since no effect was seen in TAP-1-/- cell cultures. TAP-1-/- natural killer cells or the few natural killer cells escaping the inhibitory effect of anti-class I mAb, were less cytotoxic than total B6 natural killer cells against target cell lines of different haplotype.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
In vivo demethylation of a MoMuLV retroviral vector expressing the herpes simplex thymidine kinase suicide gene by 5' azacytidine.
We constructed a functional MoMuLV-based bicistronic retroviral vector encoding the herpes simplex virus type I thymidine kinase gene, which induces sensitivity to the prodrug ganciclovir (gcv), and the reporter beta-galactosidase gene (MFG-tk-IRES-lacZ). The U937 histiocytic cell line was transduced with this vector, and a clone (VB71) with high-level transgene expression was selected. Severe combined immunodeficient (SCID) mice were injected with VB71 cells to evaluate the role of long terminal repeat methylation in transgene silencing in vivo and to see whether 5-azacytidine (5' aza-C) demethylating agent prevented it. We found 5' aza-C maintained gene expression at high level in vitro. In vivo, time to tumor onset was significantly longer in SCID mice receiving the VB71 cells, 5' aza-C, and gcv compared with animals treated with either 5' aza-C or gcv alone. The number of injected tumor cells influences tumor onset time and the efficacy of 5' aza-C and gcv treatment. The standard gcv treatment schedule (10 mg/kg from d + 1 until the onset of tumor) controlled tumor onset better than short-term treatment with high doses. In conclusion, the results extend our previous findings that transgene methylation in vivo may be prevented with an appropriate schedule of 5' aza-C and gcv.
Animals↗
TCR kappa, a new splicing of the murine TCR zeta gene locus, is modulated by glucocorticoid treatment.
T-cell receptor (TCR) is a multichain receptor in which the TCRzeta subunit is important for membrane assembly and signal transduction. Four alternative splicings of the murine TCRzeta gene locus have been previously described. We here describe a new alternative splicing of murine TCRzeta gene, TCRkappa, cloned by RT-PCR, that is encoded by exons 1-7, a portion of exon 9 and the whole exon 10 of TCRzeta gene. The protein encoded by TCRkappa mRNA is identical to that encoded by TCReta mRNA, because the stop codon is present in the exon 9 before splicing with exon 10. RNAse protection assays carried out on total RNA from thymocytes indicate that TCRkappa mRNA is 1 half with respect to TCReta mRNA, suggesting that TCRkappa mRNA contributes to determine the TCReta protein levels. The 3' untranslated region of TCRkappa mRNA is different from that of TCReta and this might lead to different t(1/2) for each species in vivo. We also show that dexamethasone (DEX), a synthetic glucocorticoid hormone, increases the amount of TCRkappa in the hybridoma T-cell line 3DO (about 5-fold increase), as indicated by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNAse protection assays. This newly described effect of DEX may constitute a further molecular mechanism that contributes to its immunomodulating activity.
Alternative Splicing↗
Natural killer cell activity and delivery: possible influence of cortisol and anesthetic agents. A study on newborn cord blood.
The aim of this study was to evaluate the influence of the method of delivery, the level of cord blood lidocaine, and the cortisol concentration on the cord blood natural killer (NK) activity in the full-term healthy newborn. We studied healthy newborns delivered by elective cesarean section without labor under general anesthesia (n = 24), delivered by cesarean section under epidural anesthesia (n = 21), and delivered vaginally with uncomplicated labor (n = 19). The NK cell activity was significantly lower in newborns delivered by cesarean section under epidural anesthesia than it was in the general anesthesia group, while it was similar to the levels found in vaginally delivered newborns. The cortisol concentration was highest in the vaginal delivery group (589.2 +/- 200 mmol/l) and lowest in the general anesthesia group (199.2 +/- 81.9 mmol/l). The mean serum lidocaine concentration was 414.1 +/- 370 microgram/l in the epidural anesthesia group and undetectable in the other groups. In conclusion, our data suggest that the cord blood NK activity was significantly influenced by the method of delivery. This effect could be related to anesthetics given to the mother for general or epidural anesthesia or to the endocrine-metabolic variations observed after different degrees of delivery-related stress. The NK cells being a first-line defense mechanism against viral infections, the results of this study suggest an association with the occurrence of early perinatal infections, especially in preterm infants.
Anesthesia, Epidural↗
Multiple gastrointestinal stromal tumors of the duodenum: case report.
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Duodenal Neoplasms↗
Hepatoid carcinoma of the stomach: is it still an unusual anatomo-clinical entity? Six cases-report.
Hepatoid carcinoma of the stomach is a rare neoplasm (especially in western countries) characterized by high levels of serum alpha-fetoprotein (AFP), the presence of "hepatoid foci" inside the gastric tumor and poor prognosis, due to the earlier onset of liver metastases. We treated six patients for hepatoid carcinoma of the stomach between 1990 and 1997. The female to male ratio was 1:1, the average age was 71 (54-81) and the average AFP-level was 1160 ng/ml (603-1531). We performed 2 total gastrectomies, 2 subtotal gastrectomies and 2 gastro-jejunostomies (due to presence of liver metastases): in one case, the patient underwent a splenectomy as well. All the tumors showed the presence of "hepatoid foci" (the morphological feature is close to the hepatocellular carcinoma) and a positive immunoreactivity to AFP. The mean survival was 3 months: only one patient is still alive and disease-free (with a 52 months follow-up). After radical surgery, she underwent a chemotherapic treatment with cisplatin, epirubicin, 5-fluorouracil and l-leucovorin. We conclude that our series (the widest in Italy and one of most impressive in Europe) confirm the poor prognosis of this neoplasm, but we also want to underline that this tumor is not so "unusual" any more and it requires new types of treatment, like postoperative chemotherapy, besides surgery, to be fighted properly.
Aged↗
Effect of lidocaine on neutrophil chemotaxis in newborn infants.
Anesthetic drugs can influence the immune system, particularly granulocyte function. The goal of the present study was to evaluate if lidocaine used for epidural anesthesia during cesarean section can influence neonatal neutrophil chemotaxis. We measured chemotaxis and plasma cord lidocaine and cortisol levels in (A) 15 infants born by cesarean section with epidural anesthesia, (B) 15 infants born by vaginal delivery, and (C) 20 infants born by cesarean section with general anesthesia. Chemotaxis levels were significantly lower in group A infants (35.5 +/- 16.1 microns) compared to groups B (54.6 +/- 10.5 microns) and C (71.4 +/- 23 microns). The highest cortisol levels were observed in vaginally delivered infants. A significant inverse relationship was observed between chemotaxis and lidocaine levels (r = -0.6, P = 0.016) in infants born by cesarean section after epidural anesthesia, while no significant correlation was observed between chemotaxis and cortisol level. In conclusion, lidocaine, transferred through the placenta to the fetus during epidural anesthesia, may have an inhibitory effect on chemotaxis.
Anesthesia, Epidural↗
Bombesin-induced pancreatic regeneration in pigs is mediated by p46Shc/p52Shc and p42/p44 mitogen-activated protein kinase upregulation.
BACKGROUND: In several animal species the pancreas has the capacity to partially regenerate in a self regulating process. A complex network of growth factors modulates this process. There is evidence that bombesin stimulates pancreatic regeneration in rodents. Whether bombesin stimulates pancreas regrowth in large mammals is unknown. Shc proteins, the target of tyrosine kinase-coupled receptors, activate p42 and p44 mitogen-activated protein (MAP) kinase and induce the transcriptional upregulation of genes involved in cell proliferation. The aims of our study were to determine whether bombesin stimulates pancreatic growth in large mammals and whether this event requires Shc-MAP kinase pathway upregulation. METHODS: Three groups of pigs were submitted to sham operation (group 1); to subtotal (70%) distal pancreatectomy (group 2), and to subtotal pancreatectomy followed by bombesin (5 mg three times daily) for 4 weeks (group 3). After a 4-week follow-up a second laparotomy was performed, and the residual pancreas removed. p46Shc, p52Shc and p66Shc, Grb2, and p42/p44 MAP kinase expression and phosphorylation were measured either in freshly isolated pancreatic acinar cells or whole pancreatic extracts. RESULTS: In vivo bombesin administration resulted in: 1) approximately 100% growth of pancreatic duodenal lobe; 2) rapid recovery from exocrine pancreatic failure; and 3) a threefold increase in the rate of pancreatic acinar cell proliferation. Incubating freshly isolated pancreatic acinar cells with bombesin resulted in time- and concentration-dependent stimulation of p46Shc/p52Shc phosphorylation, Shc-Grb2 complex formation, and p42/p44 MAP kinase activation. In vivo bombesin administration significantly upregulated p46Shc/p52Shc and MAP kinase expression and/or activity in whole pancreatic extracts. CONCLUSIONS: In vivo chronic bombesin administration stimulates pancreatic regeneration after pancreatectomy in large mammals. Bombesin-stimulated pancreatic growth is associated with upregulation of the Shc-Grb2-SOS-Ras-MAP kinase pathway.
Adaptor Proteins, Signal Transducing↗
Effect of active and passive cigarette smoking on CYP1A2-mediated phenacetin disposition in Chinese subjects.
The effect of active and passive cigarette smoking on CYP1A2-mediated phenacetin disposition was evaluated in a controlled study of 36 healthy Chinese subjects. Each subject was administered a single oral dose of phenacetin (900 mg), and frequent blood samples were taken for up to 12 hours for simultaneous high-pressure liquid chromatography determinations of plasma concentrations of phenacetin and metabolically derived paracetamol. Compared with values observed in controls not exposed to cigarette smoking, subjects who smoked 7 to 40 (median, 20) cigarettes per day exhibited a 2.5-fold higher phenacetin apparent oral clearance (7.2, 4.3-12.0 L x h(-1) x kg(-1) vs 2.9, 1.8-4.6 L x h(-1) x kg(-1) [geometric means, 95% confidence intervals]; n = 12, p < 0.05). In subjects exposed to passive smoking, phenacetin's apparent oral clearance (3.6, 2.0-46.6 L x h(-1) x kg(-1), n = 12) was intermediate between the values observed in the two other groups. Plasma paracetamol levels were moderately lower in active smokers than in passive smokers and controls. These results demonstrated that, in contrast to results found in previous studies, Chinese subjects were fully susceptible to the inducing effect of cigarette smoke on CYP1A2 activity.
Adult↗
Glucocorticoids: regulation of gene expression and apoptosis.
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Amino Acid Sequence↗
Effect of passive smoking on thyroid function in infants.
OBJECTIVE: To evaluate the effect of passive smoking on thyroid function in infants. DESIGN AND METHODS: Cord serum tri-iodiothyronine (T3), free T3 (fT3), thyroxine (T4), free T4 (fT4), TSH, thyroxine binding globulin (TBG), thyroglobulin (TG) and cord plasma thiocyanate were measured at birth, and serum TG and thiocyanate after 1 year of life, in 18 infants born from parents who did not smoke (group A), in 18 infants with a father who smoked (group B) and in 18 infants with parents both being smokers (group C). RESULTS: No significant differences were observed in cord serum concentrations of T3, fT3, T4, fT4, TSH and TBG among the three groups. Median (range) TG concentrations (ng/ml) were 30.2 (5.0-102.0), 56.3 (20.5-208.0) and 76.0 (26.0-199.0) at birth (P=0.009 for groups A and B compared; P=0.0002 for groups A and C compared), and 14.9 (5.4-32.0), 19.5 (10.0-57.5) and 20.0 (14.0-40.7) at 1 year (P=0.017 for groups A and C compared), in the three groups respectively, and thiocyanate concentrations (mmol/l) were 3.3 (0.0-51.4), 12.9 (0.0-122.2) and 27.8 (3.3-184.5) at birth (P=0.015 for groups A and C compared), and 3.1 (0.0-32.7), 6.0 (0.0-47.3) and 20.3 (0.0-230.8) at 1 year (P=0.01 for groups A and C compared) in the three groups respectively. CONCLUSIONS: TG and thiocyanate concentrations at birth and at 1 year of age in infants of smoking parents are greater than in infants with non-smoking parents. These results indicate that the change in thyroid function as evaluated by serum TG concentrations observed at birth can persist at least for 1 year if the exposure to passive smoking from both parents is continued. Increased TG concentrations may be due to a direct effect of thiocyanate on the thyroid gland.
Analysis of Variance↗
Short-term dexamethasone treatment modulates the expression of the murine TCR zeta gene locus.
Glucocorticoids (GCH) are highly effective agents in controlling inflammation and immune response. We studied the effect of the synthetic GCH dexamethasone (DEX) on the expression of TCR zeta gene splicings that code for some chains belonging to the T-cell receptor (TCR)/CD3 complex. In the DEX-treated hybridoma T-cell line 3DO, TCR zeta gene splicings increase within the first 24 hr (about fourfold increase), as demonstrated by reverse transcriptase-polymerase chain reaction and RNase protection assay. This increase is due to the stimulation of TCR zeta gene locus transcription, as demonstrated by the "run-on" assay. A similar upregulation was observed in murine thymocytes following in vivo DEX treatment. As a consequence of TCR zeta gene locus modulation, the expression of the spliced mRNAs coding for TCR zeta and TCR eta subunits is increased, whereas their relative ratio is only slightly changed. Indeed, the amount of TCR zeta protein in 24-hr DEX-treated cells is fivefold more than that in the untreated cells. A similar effect was seen in 3DO cells treated with hydrocortisone but not in those treated with testosterone. TCR zeta protein increase was confined to the cytoplasm and therefore TCR/CD3 complex expression did not increase. This newly described effect of DEX may constitute an additional molecular mechanism that contributes to its immunomodulating activity.
Animals↗
A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis.
By comparing untreated and dexamethasone-treated murine T cell hybridoma (3DO) cells by the differential display technique, we have cloned a new gene, GITR (glucocorticoid-induced tumor necrosis factor receptor family-related gene) encoding a new member of the tumor necrosis factor/nerve growth factor receptor family. GITR is a 228-amino acids type I transmembrane protein characterized by three cysteine pseudorepeats in the extracellular domain and similar to CD27 and 4-1BB in the intracellular domain. GITR resulted to be expressed in normal T lymphocytes from thymus, spleen, and lymph nodes, although no expression was detected in other nonlymphoid tissues, including brain, kidney, and liver. Furthermore, GITR expression was induced in T lymphocytes upon activation by anti-CD3 mAb, Con A, or phorbol 12-myristate 13-acetate plus Ca-ionophore treatment. The constitutive expression of a transfected GITR gene induced resistance to anti-CD3 mAb-induced apoptosis, whereas antisense GITR mRNA expression lead to increased sensitivity. The protection toward T cell receptor-induced apoptosis was specific, because other apoptotic signals (Fas triggering, dexamethasone treatment, or UV irradiation) were not modulated by GITR transfection. Thus, GITR is a new member of tumor necrosis factor/nerve growth factor receptor family involved in the regulation of T cell receptor-mediated cell death.
Amino Acid Sequence↗