SIAARTI recommendations for analgo-sedation in intensive care unit.
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Analgesia↗
Biomedical subjects
A Paolicchi
Publications and source records attributed to A Paolicchi.
Expression of gamma-glutamyltransferase in cancer cells and its significance in drug resistance.
The expression of gamma-glutamyltransferase (GGT), a cell surface enzyme involved in cellular glutathione homeostasis, is often significantly increased in human tumors, and its role in tumor progression, invasion and drug resistance has been repeatedly suggested. As GGT participates in the metabolism of cellular glutathione, its activity has been mostly regarded as a factor in reconsitution of cellular antioxidant/antitoxic defences. On this basis, an involvement of GGT expression in resistance of cancer cells to cytotoxic drugs (in particular, cisplatin and other electrophilic agents) has been envisaged. Mechanistic aspects of GGT involvement in antitumor pharmacology deserve however further investigations. Recent evidence points to a more complex role of GGT in modulation of redox equilibria, with effects acting both intracellularly and in the extracellular microenvironment. Indications exist that the protective effects of GGT may be independent of intracellular glutathione, and derive rather from processes taking place at extracellular level and involving reactions of electrophilic drugs with thiol metabolites originating from GGT-mediated cleavage of extracellular glutathione. Although expression of GGT cannot be regarded as a general mechanism of resistance, the involvement of this enzyme in modulation of redox metabolism is expected to have impact in cellular response to several cytotoxic agents. The present commentary is a survey of data concerning the role of GGT in tumor cell biology and the mechanisms of its potential involvement in tumor drug resistance.
Animals↗
Gamma-glutamyltransferase in fine-needle liver biopsies of subjects with chronic hepatitis C.
Serum gamma-glutamyltransferase (GGT) is considered as a sensitive but rather nonspecific marker of hepatobiliary disease, including chronic hepatitis C virus (HCV) infection. Although its increase in HCV infection is associated with poor response to interferon-alpha (IFN-alpha) and poor prognosis, there is little knowledge of the reasons of its increase during disease. Immunohistochemistry and enzyme histochemistry were performed on fine-needle biopsies of subjects with HCV infection. GGT was detected in the lumen of bile ducts and in bile canaliculi. Furthermore, in subjects with elevated serum GGT, immunoreactive and catalytically active GGT was also detected on the sinusoidal surface of hepatocytes and diffuse cytoplasmic positivity appeared in isolated hepatocytes and hepatocellular foci. Antigen unmasking procedures showed the presence of GGT in the cytoplasm of mature and immature bile cells and of inflammatory cells. These results suggest that during chronic HCV infection there is a general enhancement of GGT activity within the liver. As the activity of several inflammatory mediators, such as leukotrienes, nitric oxide, and interleukins is modulated by GGT activity, the present findings suggest a direct relationship between serum GGT, enhanced intrahepatic GGT activity and prognosis and therapeutic outcome of chronic HCV infection.
Biomarkers↗
Hepatocellular adenoma: imaging findings and pathological correlation.
A 45-year-old man presented with a 1-week history of gastrooesophageal reflux, epigastric discomfort and abdominal pain especially in the right hypochondrium. Abdominal ultrasonography, contrast-enhanced spiral computed tomography and magnetic resonance imaging of the abdomen were performed. Eventually, imaging findings were correlated with histopathological analysis, which confirmed the diagnosis of a 18 cm x 16 cm hepatocellular adenoma.
Adenoma, Liver Cell↗
Endogenous oxidative stress induces distinct redox forms of tumor necrosis factor receptor-1 in melanoma cells.
Receptors of the TNFR superfamily possess abundant thiols in their extracellular domains, which makes them susceptible to redox modulation by prooxidant agents and processes. Previous studies from our laboratory have documented that membrane gamma-glutamyltransferase (GGT) activity can originate reactive oxygen species in the extracellular milieu, during the GGT-mediated metabolism of extracellular glutathione. The present study was aimed thus to verify a possible redox-modulating effect of GGT activity on TNFR1 receptors. The thiol-specific probe maleimide-polyethylene glycol was used to selectively label the reduced thiol groups in proteins of cell lysates; fractions corresponding to TNFR1 were then identified by immunoblot. In human melanoma Me665/2 cells, expressing varying GGT levels, at least five distinct forms of TNFR1 have been thus identified. The more oxidized forms appear to be prevalent in the 2/60 clone, expressing higher GGT levels, as compared to clone 2/21. Stimulation of GGT activity in the latter induced an increase of the oxidized TNFR1 forms. It is conceivable that different redox states of TNFR1 may correspond to different binding affinity and/or changes in the transducing function of the receptor. As GGT is frequently expressed by malignant tumors, the described phenomena might concur to alter the sensitivity of cancer cells to agents targeted on activation of TNF-alpha-dependent signaling pathways.
Cell Line, Tumor↗
Risk factors assessment of the difficult airway: an italian survey of 1956 patients.
Over the last decade, there has been a heightened awareness and an increase in the amount of literature being published on recognition and prediction of the difficult airway. During the preoperative evaluation of the airway, a thorough history and physical specifically related to the airway should be performed. Various measurements of anatomic features and noninvasive clinical tests can be performed to enhance this assessment. In this study we correlated the Mallampati modified score and several other indexes with the laryngoscopic view to identify anatomical and clinical risk factors related to the difficult airway. We prospectively collected data on 1956 consecutive patients scheduled to receive general anesthesia requiring endotracheal intubation for elective surgery. The Mallampati classification versus the Cormack-Lehane (C-L) linear correlation index was 0.904. A Mallampati Class 3 correlated with a C-L Grade 2 (0.94), whereas a Mallampati Class 4 correlated with a C-L Grade 3 (0.85) and a C-L Grade 4 (0.80). Operator evaluation, performed by a simplified tracheal intubation difficulty scale, showed a linear correlation of 0.96 compared with the C-L groups. Although there is a correlation between oropharyngeal volume and difficult intubation, the Mallampati score by itself is insufficient for predicting difficult endotracheal intubation.
Adult↗
gamma-Glutamyl transpeptidase catalyses the extracellular detoxification of cisplatin in a human cell line derived from the proximal convoluted tubule of the kidney.
Nephrotoxicity is a side-effect and the main factor limiting the clinical use of cisplatin. In vivo, the administration of the cysteine-containing tripeptide glutathione (GSH) has been found to reduce nephrotoxicity, but the biochemical mechanism of this protective action is not fully understood. The present study was designed to gain insights into the mechanism by which GSH prevents cisplatin nephrotoxicity. We also wanted to verify the hypothesis of whether the protective action of GSH is mediated by products of the extracellular breakdown of GSH catalysed by gamma-glutamyl transpeptidase (GGT), an enzyme that is highly expressed in kidney tubular cells. The study was performed in HK-2 cells, derived from the immortalisation of human kidney proximal tubule cells. We investigated the influence of modulators of GGT activity and/or thiols on the antiproliferative activity of cisplatin and on the intracellular GSH content. We determined the antiproliferative activity of cisplatin, platinum cellular accumulation and DNA platination following precomplexing of the drug with thiols. The antiproliferative effect of cisplatin was minimally affected by the addition of GSH. However, when the antiproliferative assay was performed in the presence of glycyl-glycine (GlyGly), to serve as a transpeptidation acceptor and thus to stimulate GGT-mediated GSH catabolism, cisplatin-induced growth inhibition was largely prevented. This effect was not mediated through an increase of intracellular GSH levels, which were not affected by the GlyGly supplementation. The thiol dipeptide cysteinyl-glycine, i.e. the GSH catabolite generated by GGT activity, showed a higher reactivity against cisplatin in vitro than GSH, as was shown by the more rapid oxidation of its -SH groups. The cisplatin/GSH or cisplatin/cysteinyl-glycine adducts did not display an antiproliferative effect. However, 2 h precomplexing with GSH in the presence of GGT, or directly with the GSH catabolite cysteinyl-glycine, decreased the antiproliferative effect of cisplatin and drug-induced DNA platination to a greater extent than precomplexing with GSH alone. The results of the present study show that, in HK-2 cells, extracellular GSH decreases the antiproliferative effects of cisplatin only upon its hydrolysis by GGT, thereby supporting the hypothesis that the extracellular metabolism of GSH by GGT plays a role in modulating cisplatin nephrotoxicity. A primary role in the protection of HK-2 cells appears to be played by cysteinyl-glycine, the proximal product of the GGT-mediated hydrolysis of GSH, which shows a high reactivity against CDDP resulting in the rapid inactivation of the drug.
Antineoplastic Agents↗
SIAARTI recommendations for the treatment of postoperative pain.
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Analgesia↗
3,5,3'-Triiodothyronine deprivation affects phenotype and intracellular [Ca2+]i of human cardiomyocytes in culture.
OBJECTIVE: A decrease in plasma T3 concentration is a frequent finding in patients with heart failure. However, the role of this 'low T3 syndrome' on disease evolution has never been clarified. As phenotypic and functional cardiomyocyte impairments are alterations that correlate with the failing myocardium, we studied the long-term effects of T3 deprivation on human cardiomyocyte structure and calcium handling. METHODS: Atrial cardiomyocytes and myocardial tissue were cultured with or without 3 nM T3. Microscopical examination of structural features was followed by analysis of alpha-sarcomeric actinin and sarcoplasmic reticulum calcium ATP-ase (SERCA-2) content. Calcium handling was studied by [Ca2+](i) imaging. RESULTS: When stimulated with cyclopiazonic acid, a SERCA-2 inhibitor, T3-deprived cardiomyocytes showed significantly faster (P=0.03) and more transient (P=0.04) increases in [Ca(2+)](i) than T3-supplemented cells. Moreover, in the T3-free cultures a significantly lower number of cells (P=0.003) responded to caffeine, a typical activator of sarcoplasmic reticulum Ca(2+)-release channel. T3-deprived cardiomyocytes also presented altered morphology with larger dimensions than T3-supplemented cells (P < 0.0001). Additionally, in T3-deprived samples alpha-sarcomeric actinin and SERCA-2 protein levels were reduced to 65.6 +/- 3% (P < 0.0001) and 74.1 +/- 4% (P=0.005), respectively, when compared with the T3-supplemented group. CONCLUSIONS: Our data show that human cardiomyocyte calcium handling and phenotype are strongly influenced by T3 suggesting important implications of the 'low T3 syndrome' on the progression of heart failure.
Blotting, Western↗
Prognostic value of serum gamma-glutamyl transferase activity after myocardial infarction.
AIMS: Serum gamma-glutamyl transferase activity (gamma-GT) is able to catalyse low-density lipoprotein oxidation and has been detected in coronary atherosclerotic plaques. gamma-GT has been documented as an independent risk factor for cardiac mortality in middle-aged men. The purpose of this study is to determine the prognostic value of gamma-GT in patients with coronary artery disease. METHODS AND RESULTS: In a prospective study, gamma-GT and other cardiac risk factors were evaluated in 469 consecutive subjects with angiographically documented coronary artery disease, using mortality and mortality plus non-fatal myocardial infarction as end-points. gamma-GT showed an independent prognostic value beyond known established risk factors in the subgroup of 262 patients with previous myocardial infarction. At a 6-year follow-up, cardiac mortality was 25.2% in patients with gamma-GT >40 U x l(-1)vs 13.9% in those with gamma-GT <40 U x l(-1)(P=0.038). When both cardiac mortality and non-fatal myocardial infarction were considered as end-points, these events were recorded in 32.7% of patients with gamma-GT >40 U x l(-1)and in 20.4% of those with levels <40 U x l(-1)(P=0.031). Excess mortality and non-fatal infarction in patients with high gamma-GT levels were concentrated in the first 2 years of follow-up (P=0.014). The association of gamma-GT values >40 U x l(-1), previous myocardial infarction, and multiple vessel disease identified a subgroup of 168 patients with the highest risk of cardiac events at 6 years (P=0.024). The relationship between gamma-GT levels and cardiac events remained significant after adjustment for cardiac risk factors, and possible confounders, including alcohol consumption. gamma-GT did not show significant prognostic value in the 207 patients without previous myocardial infarction. CONCLUSION: gamma-GT is an independent cardiac risk factor in ischaemic patients with established coronary atherosclerosis and previous myocardial infarction.
Adult↗
[Quality of the postoperative course and patients' satisfaction produced by a system of postoperative pain control: postoperative clinical evidence that influences the quality of the postoperative course].
UNLABELLED: Acute pain treatment after surgery or trauma, when inadequate, contributes to increased morbidity and prolonged in hospital stay. Acute postoperative pain management can be realised by application of treatment protocols and the regular assessment of the patients clinical conditions. The aim of the ACUTE PAIN SERVICE (APS) is to plan postoperative treatment. According to our experience, besides providing assistance, the APS elaborates results and intervenes through regular audits to improve quality. This system is further enriched through collection of information obtained through an anonymous questionnaire compiled by the patients about forty eight hours after surgery. The questions are expressed such to outline a judgement about patients' satisfaction towards the services supplied by the agency. OBJECTIVE: Evaluation of effectiveness of pain treatment and level of postoperative wellbeing through continuous observation of the patient. METHODS: a retrospective study on about 4400 consecutive patients arriving at the APS in the last 2 years of activity, who have been evaluated at fixed moments using various indicators (VAS at rest/activity, PONV and other discomforts). RESULTS: Follow-up of the patients showed that: - pain relief, when reached, does not conform well-being; - for certain symptoms of discomfort, specific protocols are necessary; - there are correlations between type of surgery, type of anaesthesia and discomfort, which may be reducible through the right attitude in behaviour and therapy; - antalgic therapy itself can cause several side-effects. The solution of the discomfort problem gets close to the concept of perioperative medicine in which APS action goes beyond pain, towards a more complete pain management.
Follow-Up Studies↗
Stabilization of cytochrome P4502E1 protein by ethanol in primary hamster hepatocyte cultures.
We report the effect of ethanol on monooxygenase activities in primary hamster hepatocyte cultures maintained on collagen-coated dishes. The addition of 50mM ethanol to cell cultures both from control and ethanol pretreated animals almost completely maintained, at least for 72hr, the P4502E1-dependent aniline hydroxylase (AnH) activity and the 2E1 immunodetectable apoprotein content at the levels of the corresponding 4-hr plated hepatocytes. On the contrary, other P450-dependent monooxygenase activities, as assayed by testosterone hydroxylases, kept decreasing falling-after 72hr of culture-to the levels of the 4-hr plated hepatocytes. In both cases, in the absence of ethanol, a rapid decline of AnH activities and 2E1 apoprotein contents were also observed, attaining undetectable levels at 72hr. The hybridizable 2E1 mRNA also rapidly declined in both cultures, but such decline was not significantly altered by the presence of 50mM ethanol in the culture medium. Furthermore, we show that P4502E1 in the liver possesses a rapid degradation phase with a half-life of about 6hr. Thus, in the hamster, P4502E1 appears regulated at post-translational level, as in rat, probably by a protein stabilization mechanism.
Aniline Hydroxylase↗
Membrane gamma-glutamyl transpeptidase activity of melanoma cells: effects on cellular H(2)O(2) production, cell surface protein thiol oxidation and NF-kappa B activation status.
The metabolism of glutathione by membrane-bound &ggr;-glutamyl transpeptidase (GGT) has been recently recognized as a basal source of hydrogen peroxide in the extracellular space. Significant levels of GGT activity are expressed by malignant tumours, and in melanoma cell lines they were found to correlate with the malignant behaviour. As hydrogen peroxide and other oxidants can affect signal transduction pathways at several levels, the present study was aimed to verify: (i) the occurrence of GGT-dependent production of hydrogen peroxide in melanoma cells; (ii) the effects of GGT-dependent prooxidant reactions on known redox-sensitive cellular targets, i.e. protein thiols, the nuclear transcription factor NF-kappa B and p53. Two melanoma Me665/2 cell clones, exhibiting traces of (clone 2/21) or high (clone 2/60) GGT activity, were studied. The occurrence of GGT-dependent production of hydrogen peroxide was apparent in 2/60 cells, in which it was accompanied by lower levels of cell surface protein thiols. In 2/60 cells, GGT expression was also associated with higher levels of NF-kappa B activation, as compared to GGT-poor 2/21 cell clone. Indeed, stimulation or inhibition of GGT activity in 2/60 cells resulted in progressive activation or inactivation of NF-kappa B, respectively. An analysis of the p53 gene product indicated lack of protein expression in 2/60 cells, whereas a mutant protein was highly expressed in 2/21 cells. Taken together, these results indicate that the expression of GGT activity can provide melanoma cells with an additional source of hydrogen peroxide, and that such prooxidant reactions are capable to modify protein thiols at the cell surface level. In addition, GGT expression results in an up-regulation of the transcription factor NF-kappa B, which could explain the higher metastatic behaviour reported for GGT-rich melanoma cells as compared to their GGT-poor counterparts.
Blotting, Western↗
Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of gamma-glutamyl transpeptidase-dependent H2O2 production and S-thiolation.
The expression of gamma-glutamyl transpeptidase (GGT), a plasma membrane ectoenzyme involved in the metabolism of extracellular reduced glutathione (GSH), is a marker of neoplastic progression in several experimental models, and occurs in a number of human malignant neoplasms and their metastases. Because it favors the supply of precursors for the synthesis of GSH, GGT expression has been interpreted as a member in cellular antioxidant defense systems. However, thiol metabolites generated at the cell surface during GGT activity can induce prooxidant reactions, leading to production of free radical oxidant species. The present study was designed to characterize the prooxidant reactions occurring during GGT ectoactivity, and their possible effects on the thiol redox status of proteins of the cell surface. Results indicate that: (i) in U937 cells, expressing significant amounts of membrane-bound GGT, GGT-mediated metabolism of GSH is coupled with the extracellular production of hydrogen peroxide; (ii) GGT activity also results in decreased levels of protein thiols at the cell surface; (iii) GGT-dependent decrease in protein thiols is due to sulfhydryl oxidation and protein S-thiolation reactions; and (iv) GGT irreversible inhibition by acivicin is sufficient to produce an increase of protein thiols at the cell surface. Membrane receptors and transcription factors have been shown to possess critical thiols involved in the transduction of proliferative signals. Furthermore, it was suggested that S-thiolation of cellular proteins may represent a mechanism for protection of vulnerable thiols against irreversible damage by prooxidant agents. Thus, the findings reported here provide additional explanations for the envisaged role played by membrane-bound GGT activity in the proliferative attitude of malignant cells and their resistance to prooxidant drugs and radiation therapy.
Fluorescent Dyes↗
Hydrogen peroxide produced during gamma-glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells.
It has been reported in several cell lines that exposure to low levels of reactive oxygen species can exert a stimulatory effect on their proliferation. We have previously shown that mild oxidative conditions can also counteract apoptotic stimuli. A constitutive cellular production of low levels of superoxide and hydrogen peroxide originates from various sources; among these, gamma-glutamyl transpeptidase (GGT), the plasma membrane-bound activity in charge of metabolizing extracellular reduced glutathione, has recently been included. Since the inhibition of GGT is a sufficient stimulus for the induction of apoptosis in selected cell lines, we investigated whether this effect might result from the suppression of the mentioned GGT-dependent prooxidant reactions, on the theory that the latter may represent a basal antiapoptotic and proliferative signal for the cell. Experiments showed that: 1) GGT activity in U937 monoblastoid cells is associated with the production of low levels of hydrogen peroxide, and two independent GGT inhibitors cause a dose-dependent decrease of such GGT-dependent production of H2O2; 2) GGT inhibition with acivicin results in cell growth arrest, and induces cell death and DNA fragmentation with the ladder appearance of apoptosis; 3) treatment of cells with catalase--and even more with Trolox C--is able to decrease their proliferative rate; 4) GGT inhibition (with suppression of H2O2 production) results in a down-regulation of poly(ADP-ribose) polimerase (PARP) activity, which precedes the proteolytic cleavage of PARP molecule, such as that typically induced by caspases. The reported data suggest that the low H2O2 levels originating as a by-product during GGT activity are able to act as sort of a 'life signal' in U937 cells, insofar as they can maintain cell proliferation and protect against apoptosis, possibly through an up-regulation of PARP activity.
Antioxidants↗
Gamma-glutamyl transpeptidase-dependent iron reduction and LDL oxidation--a potential mechanism in atherosclerosis.
BACKGROUND: gamma-Glutamyl transpeptidase (gamma-GT) is found in serum and in the plasma membranes of virtually all cell types. Its physiologic role is to initiate the hydrolysis of extracellular glutathione (GSH), a tripeptide in which cysteine lies between alpha-glycine and gamma-glutamate residues. Cysteine and other thiol compounds are known to promote LDL oxidation by reducing Fe(III) to redox active Fe(II); therefore, we sought to determine whether similar reactions can be sustained by GSH and influenced by gamma-GT. METHODS: Fe(III) reduction and LDL oxidation were studied by monitoring the formation bathophenanthroline-chelatable Fe(II) and the accumulation of thiobarbituric acid-reactive substances, respectively. Human atheromatous tissues were examined by histochemical techniques for the presence of oxidized LDL and their colocalization with cells expressing gamma-GT activity. RESULTS: A series of experiments showed that the gamma-glutamate residue of GSH affected interactions of the juxtaposed cysteine thiol with iron, precluding Fe(III) reduction and hence LDL oxidation. Both processes increased remarkably after addition of purified gamma-GT, which acts by removing the gamma-glutamate residue. GSH-dependent LDL oxidation was similarly promoted by gamma-GT associated with the plasma membrane of human monoblastoid cells, and this process required iron traces that can be found in advanced or late stage atheromas. Collectively, these findings suggested a possible role for gamma-GT in the cellular processes of LDL oxidation and atherogenesis. Histochemical analyses confirmed that this may be the case, showing that gamma-GT activity is expressed by macrophage-derived foam cells within human atheromas, and that these cells colocalize with oxidized LDL. CONCLUSIONS: Biochemical and histochemical correlates indicate that gamma-GT can promote LDL oxidation by hydrolyzing GSH into more potent iron reductants. These findings may provide mechanistic clues to the epidemiologic evidence for a possible correlation between persistent elevation of gamma-GT and the risk of fatal reinfarction in patients with ischemic heart disease.
Adult↗
[Superficial cervical plexus block in association with laryngeal mask in parathyroid surgery].
Superficial cervical plexus block in association with laryngeal mask for the airways control has improved the postoperative outcome, in comparison with a previous group in general anaesthesia, performed by the same equipment. The local anaesthetic infiltration as a preemptive analgesia give us good evidences in pain control. The laryngeal mask contributes to a good surgical field and avoid the neck hypertension.
Cervical Plexus↗
Detection of colorectal liver metastases: prospective comparison of unenhanced and ferumoxides-enhanced magnetic resonance imaging at 1.5 T, dual-phase spiral CT, and spiral CT during arterial portography.
The purpose of this study was to compare the efficacy of unenhanced and ferumoxides-enhanced magnetic resonance imaging with that of dual-phase spiral CT and spiral CT during arterial portography (CTAP) for the detection of colorectal liver metastases. Fourteen patients with liver metastases candidates for partial hepatectomy were examined with dual-phase spiral CT, unenhanced and ferumoxides-enhanced MR imaging at 1.5 T, and spiral CTAP. Imaging tests were read blinded, prospectively, quantitating number of lesions excepting CTAP which used US to exclude cysts. Subsequent intraoperative US and pathologic findings were correlated with preoperative imaging results. At surgery, 36 lesions 0.5-13 cm in diameter (mean+/-standard deviation, 2.9+/-2.1 cm) were identified. Dual-phase spiral CT depicted 21/36 (58%); precontrast MR imaging, 19/36 (53%); ferumoxides-enhanced MR imaging, 30/36 (83%); and spiral CTAP, 34/36 (94%) lesions. Ferumoxides-enhanced MR imaging was significantly more sensitive than spiral CT and unenhanced MR imaging (P < 0.01). The difference in sensitivity between ferumoxides-enhanced MR imaging and spiral CTAP was not statistically significant (P> 0.1). Spiral CTAP, however, depicted nine false-positive lesions (2 hemangiomas, 7 perfusion defects). The positive predictive value was 79% for spiral CTAP and 100% for combined pre- and postcontrast MR imaging. We conclude that ferumoxides-enhanced MR imaging is superior to unenhanced MR imaging and biphasic spiral CT for depiction of colorectal liver metastases. Further investigation is needed to clarify whether MR imaging with use of ferumoxides might replace spiral CTAP for preoperative evaluation of liver resection candidates.
Adult↗