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Biomedical subjects

M Costanzo

Publications and source records attributed to M Costanzo.

At least 19 recordsLinked to original sources
PubMed2003

Interleukin-6 release in the hepatic blood outflow during normothermic liver ischaemia in humans.

BACKGROUND: Liver surgery techniques have consistently improved and normothermic ischaemia of the liver is considered to be a safe procedure to reduce intraoperative haemorrhage. Hepatic failure, however, remains a significant complication. In liver ischaemia-reperfusion injury, cytokines play a key proinflammatory role. Cytokines may be part of the intercellular signalling that leads to recovery or to failure after major surgery. Moreover, they could be potential predictors of the outcome. Modulation of the pattern of cytokine response in the early postsurgery period could represent a new approach to minimise the impact of these procedures. AIMS: The aim of our study was to analyse the cytokine pattern in the hepatic blood outflow in patients undergoing surgical intervention of partial liver resection with clamping of the hepatic pedicle and liver ischaemia, and to correlate the cytokine behaviour with clinical parameters. PATIENTS: We studied eight patients (mean age 55 years) who underwent surgical intervention of liver resection during vascular exclusion of the hepatic pedicle. Patients were monitored for haemodynamic and haematological parameters during the pre-, infra- and postoperative period. METHODS: IL-I alpha, IL-6, TNF-alpha and IFN-gamma were assayed from peripheral and central vein blood at different times. Blood samples for cytokine assays were also drawn from the supra-hepatic veins after clamping of the porta hepatis. RESULTS: We found a significant increase of the IL-6 levels in the supra-hepatic samples during liver ischaemia, while the trend with IL-1alpha was less clear; IFN-gamma and TNF-alpha were undetectable with the methods used. IL-6 levels appeared to correlate positively with bilirubin and gamma-GT levels and negatively with the degree of acidosis. CONCLUSIONS: Our study confirms that during surgical ischaemic stress there is an increase of IL-6 serum levels more relevant in supra-hepatic vein blood. Cytokines could contribute to modulate the inflammatory response to liver ischaemia.

Adult↗
PubMed2003

An update on the medical treatment of Crohn's disease.

Crohn's disease (CD) is a chronic transmural inflammation that may involve any part of the alimentary tract. The affected patients show peculiar metabolic characteristics; they often have a reduced body weight, due to reduction of lipid stores (in spite of lean mass depletion) and an increased utilization of lipids as fuel substrate. An alteration of nutritional status, up to real malnutrition, is common in CD and malnutrition's effects influence the course of disease, acting as independent factors. We will give a description of the main pharmacological approaches in CD management; the first line therapy for CD patients remains the combinations of aminosalicylates, antibiotics, corticosteroids and immunomodulatory agents. The development of new biological agents for the treatment of inflammatory bowel diseases has added to the growing armamentarium of available therapy. We also will explain the importance of enteral nutrition, whose importance goes over the simple amelioration of nutritional status, especially in childhood CD, where it has shown to be as effective as traditional therapy.

Adjuvants, Immunologic↗
PubMed2002

A case of severe hypertension caused by ACTH-independent macronodular adrenal hyperplasia.

This report describes a rare case of ACTH-independent macronodular adrenal hyperplasia (AIMAH) arisen with symptomatic severe hypertension and hypokaliemia. A 55-year-old man was admitted to hospital with a clinical picture characterized by several episodes of transient ischemic attacks (TIA) and right hemiplegia, related to severe arterial hypertension. Laboratory tests showed urinary levels of catecholamines, metanephrines and vanillylmandelic acid (VMA) in normal range; high urinary free cortisol excretion, elevated serum cortisol with loss of the circadian rhythm and low ACTH plasma levels. ACTH failed to respond to CRH administration. Serum cortisol levels were not modified after high doses of dexamethasone. MRI showed bilateral macronodular hyperplasia of adrenal glands, whereas pituitary-MRI did not show tumoral lesions. Therefore, ACTH-independent macronodular hyperplasia was suspected. Though obese, the patient had no typical Cushing habit, and symptomatic hypertension with hypokaliemia was the only clinical evidence for this rare kind of Cushing's syndrome. After obtaining a satisfactory control of blood pressure, the patient was successfully submitted to laparoscopic bilateral adrenalectomy and underwent complete clinical remission. The histology showed adrenal macronodular hyperplasia. During the twenty-four month follow-up, the patient had no further transient ischemic attacks or need of glucocorticoid replacement therapy and withdrew the antihypertensive drugs.

Adrenal Glands↗
PubMed2000

Modulation of X-ray-induced damage recognition and repair in ageing human peripheral blood mononuclear cells by an interleukin-6-type cytokine.

We have investigated the effects of an interleukin (IL)-6-type cytokine on the DNA-binding activity of ku and on unscheduled DNA repair in X-ray-treated peripheral blood mononuclear cells (PBMC) from human subjects of different ages. The cytokine used, called K-7/D-6, is an IL-6 variant with increased in vivo and in vitro biological activity compared to the wild type molecule. Ku is the DNA-binding component of the DNA-dependent protein kinase (DNA-PK). It binds the ends of various types of DNA discontinuity and is involved in the repair of DNA breaks caused by V(D)J recombination, isotype switching, physiological oxidation reactions, ionizing radiation and some chemotherapeutic drugs. The ku-dependent repair process, called non-homologous end joining, is the main DNA double strand break repair mechanism in irradiated mammalian cells. Results show that K-7/D-6 significantly increases DNA-binding activity of ku in irradiated PBMC from young but not from elderly subjects. However, K-7/D-6 is able to induce unscheduled DNA repair in irradiated PBMC from both young and elderly subjects. These effects of K-7/D-6 are relevant to the mechanisms of the cellular response to DNA damage.

Adult↗
PubMed2000

The protease-activated receptor 2 regulates pigmentation via keratinocyte-melanocyte interactions.

Close association exists between melanocytes, the pigment melanin-producing cells in the body, and their neighboring keratinocytes. Keratinocytes are the pigment recipients and skin pigmentation is the result of this interaction. While the chemical basis of melanin production (melanogenesis) is well documented, the molecular mechanism of melanosome transfer needs to be elucidated. We are now providing first evidence that the protease-activated receptor 2 (PAR-2) expressed on keratinocytes, but not on melanocytes, is involved in melanosome transfer and therefore may regulate pigmentation. Activation of PAR-2 with trypsin or with the peptide agonist SLIGRL induced pigmentation in both two- and three-dimensional cocultures of keratinocytes and melanocytes, but not in cocultures that were spatially separated, indicating the need for intimate cell-cell contact. Topical application of SLIGRL on human skin transplanted on SCID mice resulted in a visible skin darkening. Histological examination revealed increased deposits of melanin in the keratinocytes. Inhibition of PAR-2 activation by RWJ-50353, a serine protease inhibitor, resulted in depigmentation and changes in expression of melanogenic-specific genes. Keratinocyte-melanocyte contact was essential for this depigmenting effect. Topical application of this inhibitor induced lightening of the dark skin Yucatan swine, which was confirmed by histochemical analysis. The results presented here suggest a novel mechanism for the regulation of pigmentation, mediated by the activation or inhibition of the keratinocyte receptor PAR-2.

Animals↗
PubMed2000

Inhibition of melanosome transfer results in skin lightening.

The chemical basis of melanogenesis is well documented, but the mechanism of melanosome transfer and the regulation of pigmentation by keratinocyte-melanocyte interactions are not well understood. Therefore we examined the effects of serine protease inhibitors on skin pigmentation and found that the protease-activated receptor 2, expressed on keratinocytes, may regulate pigmentation via keratinocyte-melanocyte interactions. Here we show that modulation of protease-activated receptor 2 activation affects melanosome transfer into keratinocytes, resulting in changes in pigment production and deposition. SLIGRL, the protease-activated receptor 2 activating peptide, enhanced melanosome ingestion by keratinocytes, thus increasing pigment deposition. RWJ-50353, a serine protease inhibitor, led to reduced pigment deposition in melanocytes and depigmentation. Electron microscopy studies illustrated an accumulation of immature melanosomes inside melanocytes and abnormal dendrite dynamics in RWJ-50353-treated epidermal equivalents. RWJ-50353 induced a visible and dose-dependent skin lightening effect in the dark-skinned Yucatan swine. Examinations by electron microscopy indicated that the in vivo transfer of melanosomes from melanocytes to keratinocytes was affected. Our data suggest that modulation of keratinocyte-melanocyte interactions via the protease-activated receptor 2 pathway affects melanosome transfer. The use of RWJ-50353 to modulate protease-activated receptor 2 activation could lead to a new class of depigmenting agents.

Animals↗
PubMed1999

Effect of age on DNA binding of the ku protein in irradiated human peripheral blood mononuclear cells (PBMC).

DNA binding of the ku protein was investigated in peripheral blood mononuclear cells (PBMC) from 24 subjects of different ages (20-89 years old) displaying age-related changes in DNA repair, mitotic responsiveness, and cytokine production. Ku is an heterodimeric protein composed of two subunits of 70 and 80 kDa, which is involved in the earliest steps of DNA damage recognition. DNA binding of ku 70/80 was found unchanged in normal PBMC from aging subjects but progressively declined in x-ray-irradiated PBMC from young to adult, and elderly subjects. This finding was concomitant with the age-related fall of DNA repair in the whole population.

Adult↗
PubMed1999

Characteristics of gastric-vein lymphocytes with regard to the immune response to Helicobacter pylori.

BACKGROUND: Between peripheral blood and tissue-infiltrating lymphocytes there is an intermediate compartment, the blood of the organ-draining vessels, which could show unusual features. The aim of the present study was to analyse the characteristics of the lymphocytes from the stomach-draining vessels and the cytokine secretion by these lymphocytes. The CagA-mediated lymphocyte activation in Helicobacter pylori-infected subjects and the humoral response to this antigen were evaluated and correlated with clinical data. METHODS: We studied lymphocyte proliferation either with mitogens or with the CagA antigen and cytokine production and IgG anti-CagA by means of an enzyme-linked immunosorbent assay in peripheral blood and gastric-vein blood obtained during surgical intervention. RESULTS: We showed higher proliferative response and cytokine production in lymphocytes from the gastric vein. The mitogenic response to the CagA antigen was highly specific but poorly sensitive for the H. pylori infection in both the compartments. The overall cytokine profile in our patients affected by non-ulcer disease was of the Th0 type. CONCLUSIONS: Gastric-vein-derived lymphocytes seem to show unusual features, as they behave like peripheral blood lymphocytes but show higher responses to all the tested stimuli. It is possible that the interaction of the lymphocytes with the mucosal environment could activate the synthetic mechanisms, making the cells more 'responsive' to the stimulation. The CagA antigen is able to induce a specific T-lymphocyte response and is therefore a valid candidate antigen for the development of a vaccine.

Adult↗
PubMed1999

Regulation of transcription at the Saccharomyces cerevisiae start transition by Stb1, a Swi6-binding protein.

In Saccharomyces cerevisiae, gene expression in the late G(1) phase is activated by two transcription factors, SBF and MBF. SBF contains the Swi4 and Swi6 proteins and activates the transcription of G(1) cyclin genes, cell wall biosynthesis genes, and the HO gene. MBF is composed of Mbp1 and Swi6 and activates the transcription of genes required for DNA synthesis. Mbp1 and Swi4 are the DNA binding subunits for MBF and SBF, while the common subunit, Swi6, is presumed to play a regulatory role in both complexes. We show that Stb1, a protein first identified in a two-hybrid screen with the transcriptional repressor Sin3, binds Swi6 in vitro. The STB1 transcript was cell cycle periodic and peaked in late G(1) phase. In vivo accumulation of Stb1 phosphoforms was dependent on CLN1, CLN2, and CLN3, which encode G(1)-specific cyclins for the cyclin-dependent kinase Cdc28, and Stb1 was phosphorylated by Cln-Cdc28 kinases in vitro. Deletion of STB1 caused an exacerbated delay in G(1) progression and the onset of Start transcription in a cln3Delta strain. Our results suggest a role for STB1 in controlling the timing of Start transcription that is revealed in the absence of the G(1) regulator CLN3, and they implicate Stb1 as an in vivo target of G(1)-specific cyclin-dependent kinases.

Blotting, Western↗
PubMed1998

A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators.

BACKGROUND: After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS: In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS: Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS: Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Aged↗
PubMed1998

Changes in the amount and level of phosphorylation of p56(lck) in PBL from aging humans.

The effects of aging on the activation of the cytoplasmic tyrosine protein kinase p56(lck) have been investigated in PBL from adult and elderly subjects upon activation with mitogens or different co-stimuli. Results show that the amount and phosphorylation of p56(lck) are reduced in PBL from elderly as compared to adult subjects. This finding suggests that alterations in p56(lck) may contribute to the age-associated loss of some T cell functions, such as proliferation and IL-2 production, which are found decreased in PBL from old individuals. However, p56(lck) seems irrelevant to the production of IFN-gamma and IL-4 which were both found increased in the PBL from old subjects, as expected from the relative expansion of memory versus naive T cell subpopulations in aging.

Adult↗
PubMed1998

Cell proliferation and ku protein expression in ageing humans.

Previous studies on DNA repair in ageing have demonstrated increased frequencies of single and double strand breaks in lymphocytes from elderly subjects and, as a consequence, decreased efficiency in DNA replication. We have investigated the relationship between cell proliferation and the nuclear expression of ku protein in a human population of 43 subjects of different ages. Ku is an heterodimeric protein composed of two subunits of 70 and 80 kDa, which is involved in the early steps of DNA damage recognition. In the present study, PBL from subjects of different ages were PHA-activated to evaluate the stimulation index and the production of Th1- and Th2-type cytokines. Moreover, nuclear extracts were obtained from activated lymphocytes to evaluate by a gel retardation assay the presence and the functional activity of the heterodimer ku 70/80. Our results indicate that ageing affects the mitotic responsiveness and cytokine production to a significant extent, but only marginally the expression of ku 70/80. These findings suggest that the age-related impairment in DNA repair mechanisms are only in part related to the reduced expression of ku protein able to recognize DNA damage.

Adult↗
PubMed1997

Effects of estrogen replacement therapy on thrombin generation.

The aim of this study was to investigate the hemostatic system in menopausal women before and after three months of treatment with transdermal estradiol (TTS 50, 50 micrograms/die, n = 13) or coniugated equine estrogen (CEE, 0.625 mg/die, n = 9) by evaluating : beta-thromboglobulin, platelet factor 4, factor VIIag, factor VIIc, fibrinopeptide A-FPA-, thrombin-antithrombin-TAT-complexes, antithrombin-AT-activity, protein C, plasma fibrinolytic activity (euglobulin clot lysis time), plasminogen and antiplasmin activity. FPA levels significantly increased during TTS 50 treatment (p < 0.001) while protein C showed a slight but significant decrease in both treatments (TTS 50 p < 0.001, CEE p < 0.05). TAT complexes and AT were found unaltered. Platelet function and fibrinolytic activity did not significantly change. A significant relationship between FPA and estradiol levels, which were significantly increased during. TTS 50 therapy, was found (r = 0.40, p < 0.05). These findings indicate that unopposed estradiol given by transdermal route induces a slight but significant blood clotting activation, which seems strictly related to its biological activity.

Administration, Cutaneous↗
PubMed1994

Interactions between substituted tryptamine analogues, MAO inhibitors and cytochrome P-450.

The effects of some MAO inhibitors, N-acetylenic analogues of tryptamine, on rat liver microsomal cytochrome P-450 (cyt P-450) have been investigated. All the compounds tested interacted with cyt P-450 with Ks values ranging between 14 and 358 microM (clorgyline Ks = 10.5 microM). Compounds with a tertiary amine and those possessing a secondary amine group in the acetylenic side chain exhibited type I and type II difference spectra, respectively. Aniline hydroxylase activity was inhibited irreversibly and in a time-dependent fashion by all compounds tested with IC50 ranging between 7 x 10(-5) and 7 x 10(-3) M (clorgyline 10(-4) M).

Animals↗
PubMed1994

Relationships of Na+ and K+ concentrations to GRP, CGRP, and calcitonin immunoreactivities and Na+,K(+)-ATPase (NKA) inhibitory activity in human breast cyst fluid.

BACKGROUND: Although the etiology of gross cystic disease of the breast is unknown, elevated cyst concentrations of potassium (K+) (> 60 mM/L) may be related to symptoms. The purpose of this study was to clarify the mechanism(s) of K+ accumulation in breast cysts. METHODS: We assayed cyst fluids for factors known to exert effects on K+ transport, namely, endogenous digitalis-like inhibitors of Na+,K(+)-ATPase (NKA) and the neuropeptides gastrin-releasing peptide (GRP), calcitonin (CT), and calcitonin gene-related peptide (CGRP). RESULTS: Cyst fluid K+ was directly correlated with cyst volume, cyst NKA inhibitory activity (in ouabain equivalents), and cyst concentrations of calcitonin, GRP, and CGRP. Cyst fluid Na+ was inversely correlated with cyst fluid K+, cyst NKA inhibitory activity, cyst volume, and cyst fluid concentrations of calcitonin, GRP, and CGRP. NKA inhibitory activity correlated directly with GRP and CGRP. Immunocytochemistry localized GRP to breast cyst lining cells and areas of ductal and lobular epithelial hyperplasia in biopsies of 15 of 15 cysts and in 5 of 5 breast carcinomas, but not in (0 of 5) normal breast biopsies. Specificity of GRP staining was demonstrated by total abolition of reactivity after adsorption with synthetic GRP, but not after adsorption with synthetic substance P, neurokinin A, or neurokinin B. CONCLUSIONS: We conclude that both the concentrations of endogenous digitalis-like factors and the neuropeptides calcitonin, GRP, and CGRP in human breast cyst fluids are related to the concentrations of K+ and Na+ in breast cysts and to cyst volume.

Adult↗
PubMed1994

Neuroinvasion and persistence of human herpesvirus 6 in children.

Human herpesvirus 6 (HHV-6) causes a febrile illness in children and has been implicated as a cause of encephalitis and recurrent seizures. Paired samples of cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMC) from 487 children were evaluated by nested polymerase chain reaction (PCR) for evidence of current or past infection with HHV-6. PBMC were also cultured for isolation of HHV-6. These data were correlated with the patients' clinical information. HHV-6 DNA was detected in 72 (14.8%) of 487 CSF samples. HHV-6 persistence was documented in 142 children by PCR detection of HHV-6 DNA in PBMC or CSF (or both) in the absence of primary HHV-6 infection; the central nervous system was the only site of HHV-6 DNA persistence in 28.9%. HHV-6 DNA can be detected in the CSF of children during and after primary infection, and the central nervous system may be the sole site of persistence.

Child, Preschool↗
PubMed1994

Interactions of monoamine oxidase inhibitors, N-acetylenic analogues of tryptamine, with rat liver microsomal cytochrome P450.

Interactions between some novel and potent monoamine oxidase inhibitors (MAOIs), acetylenic analogues of tryptamine, and rat liver microsomal cytochrome P450 (P450) as evidenced by visible spectra analysis were analysed. Compounds with a secondary aliphatic amine moiety throughout induced type II difference spectra and exhibited the highest affinity for P450, whereas tertiary amines induced type I spectral changes and showed diminished affinity. P450 dependent aniline hydroxylase activity was inhibited by all compounds in an irreversible time-dependent manner. Only tertiary aliphatic amines constituted the substrate for P450-dependent N-demethylase activity, with comparable kinetic parameters. The N-demethylated metabolites were identified by thin-layer chromatography and mass-spectrometric analyses. These findings describe the role of P450-dependent microsomal mono-oxygenase systems in the metabolism of some MAOI acetylenic tryptamine derivatives and the possible hepatic contribution to adverse interactions between MAOIs, endobiotics and sympathomimetic compounds.

Acetylene↗