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Biomedical subjects

C Giannini

Publications and source records attributed to C Giannini.

At least 19 recordsLinked to original sources
PubMed2007

Modifications of plasma platelet-activating factor (PAF)-acetylhydrolase/PAF system activity in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) chronically infects about 200 million individuals worldwide and leads to severe liver and lymphatic diseases. HCV circulates in the serum, associated with apoB-containing lipoproteins. Platelet-activating factor (PAF), a pro-inflammatory mediator, is mainly modulated by plasma PAF-acetylhydrolase (pPAF-AH), associated with ApoB100-containing low-density lipoproteins (LDL). The aim of the study was to evaluate the potential effects of chronic HCV infection on the PAF/pPAF-AH system. HCV-RNA was detected in plasma, peripheral blood mononuclear cells (PBMC) and liver samples. Plasma PAF levels, pPAF-AH activity, ApoB100 serum titres and pPAF-AH mRNA levels in cultured macrophages were determined. Plasma PAF levels were significantly higher and pPAF-AH activity was significantly lower in HCV patients than in controls. No significant modifications of pPAF-AH mRNA in macrophages or in ApoB100 values were observed in HCV patients compared with controls. Patients who cleared HCV after antiviral treatment showed a complete restoration of pPAF-AH activity and significant decrease of PAF levels during the follow-up. No data exist about the PAF/pPAF-AH system behaviour during HCV infection. This study shows that in HCV patients modifications of pPAF-AH activity/PAF levels take place and that HCV clearance restored pPAF-AH activity. This suggests that circulating viral particles play a role in PAF/pPAF-AH system modifications and such an alteration could be involved in HCV-related damage.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Engineering of bone using bone marrow stromal cells and a silicon-stabilized tricalcium phosphate bioceramic: evidence for a coupling between bone formation and scaffold resorption.

Resorbable porous ceramic constructs, based on silicon-stabilized tricalcium phosphate, were implanted in critical-size defects of sheep tibias, either alone or after seeding with bone marrow stromal cells (BMSC). Only BMSC-loaded ceramics displayed a progressive scaffold resorption, coincident with new bone deposition. To investigate the coupled mechanisms of bone formation and scaffold resorption, X-ray computed microtomography (muCT) with synchrotron radiation was performed on BMSC-seeded ceramic cubes. These were analyzed before and after implantation in immunodeficient mice for 2 or 6 months. With increasing implantation time, scaffold thickness significantly decreased while bone thickness increased. The muCT data evidenced that all scaffolds showed a uniform density distribution before implantation. Areas of different segregated densities were instead observed, in the same scaffolds, once seeded with cells and implanted in vivo. A detailed muX-ray diffraction analysis revealed that only in the contact areas between deposited bone and scaffold, the TCP component of the biomaterial decreased much faster than the HA component. This event did not occur at areas away from the bone surface, highlighting coupling and cell-dependency of the resorption and matrix deposition mechanisms. Moreover, in scaffolds implanted without cells, both the ceramic density and the TCP:HA ratio remained unchanged with respect to the pre-implantation analysis.

Animals↗
PubMed2006

Macroangiopathy in adults and children with diabetes: from molecular mechanisms to vascular damage (part 1).

Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia PER SE and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.

Adult↗
PubMed2006

Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients.

Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (TRP) metabolism, is induced in various tissues of patients with bacterial and viral infection or with neoplastic diseases. This induction is considered the main cause of the decreased serum TRP levels, the reduced brain serotonin synthesis and the occurrence of psychopathological disorders often detected in patients with chronic infections or different forms of cancer. We studied 89 subjects including: (a) 39 patients with chronic hepatitis C virus (HCV) infection and mild liver damage (b) 40 healthy controls, and (c) 10 patients with chronic hepatitis B virus (HBV) infection. We measured serum TRP and kynurenine levels and IDO activity in macrophages. Furthermore, each patient had an accurate psychopathological evaluation. HCV-infected patients had lower (-28%) serum TRP concentrations than healthy volunteers or HBV-infected patients with comparable liver damage. Depression and anxiety symptoms were particularly common in HCV patients. Unexpectedly, serum kynurenine levels and IDO activity in cultured macrophages (under both basal or stimulated conditions) were lower in HCV patients than in controls. Our study shows that HCV patients have reduced serum TRP levels and confirms that they frequently suffer from anxiety and depression-related symptoms. The reduced IDO activity found in the macrophages of these patients suggest that HCV infection may hamper macrophage functions.

Adult↗
PubMed2004

Bilateral generalized polymicrogyria (BGP): a distinct syndrome of cortical malformation.

BACKGROUND: Syndromes of bilateral symmetric polymicrogyria include an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP), in which the malformation is most severe rostrally. The authors describe a new syndrome they have termed "bilateral generalized polymicrogyria" (BGP), in which the malformation occurs in a generalized distribution but is often most severe in the perisylvian regions. METHODS: Patients with bilateral polymicrogyria were identified from multiple medical centers worldwide. The diagnosis of BGP was based on findings from conventional spin echo MRI and, in one case, postmortem neuropathologic findings. Genetic analysis was performed for those patients from consanguineous pedigrees and those with multiple affected siblings to rule out linkage to the BFPP locus on chromosome 16q. RESULTS: Twelve patients were identified with BGP. Clinical features included cognitive and motor delay as well as seizures. Some specific features characteristic of other known bilateral polymicrogyria syndromes, such as pseudobulbar palsy and dysconjugate gaze, were not commonly seen in these patients. Radiologically, polymicrogyria appeared widespread but was often most severe in the perisylvian regions. Pathologic examination in one case revealed a diffusely thin and excessively folded cerebral cortex lacking normal six-layered architecture. Seven patients subjected to genetic analysis did not demonstrate linkage to the BFPP locus. CONCLUSIONS: BGP is a distinct syndrome of cortical malformation. Several features allow BGP to be distinguished from other disorders on the growing list of bilateral symmetric polymicrogyria syndromes.

Abnormalities, Multiple↗
PubMed2003

The AXH module: an independently folded domain common to ataxin-1 and HBP1.

Ataxin-1 (ATX1), a human protein responsible for spinocerebellar ataxia type 1 in humans, shares a region of homology, named AXH module, with the apparently unrelated transcription factor HBP1. Here, we describe the first characterisation of the AXH module in terms of its structural properties and stability. By producing protein constructs spanning the AXH modules of ATX1 and HBP1 and by comparing their properties, we have identified the minimal region sufficient for forming independently folded units (domains). Knowledge of the AXH domain boundaries allows us to map many of the interactions of ATX1 with other molecules onto the AXH module. We further show that the AXH of ATX1 is a dimerisation domain and is able to recognise RNA with the same nucleotide preference previously described for the full-length protein. AXH is therefore a novel protein-protein and RNA binding motif.

Amino Acid Motifs↗
PubMed2003

Hepatitis C virus biology.

Hepatitis C virus infection represents a major problem of public health with around 350 millions of chronically infected individuals worldwide. The frequent evolution towards severe liver disease and cancer are the main features of HCV chronic infection. Antiviral therapies, mainly based on the combination of IFN and ribavirin can only assure a long term eradication of the virus in less than half of treated patients. The mechanisms underlying HCV pathogenesis and persistence in the host are still largely unknown and the efforts made by researchers in the understanding the viral biology have been hampered by the absence of a reliable in vitro and in vivo system reproducing HCV infection. The present review will mainly focus on viral pathogenetic mechanisms based on the interaction of HCV proteins (especially core, NS3 and NS5A) with host cellular signaling transduction pathways regulating cell growth and viability and on the strategies developed by the virus to persist in the host and escape to antiviral therapy. Past and recent data obtained in this field with different experimental approaches will be discussed.

Animals↗
PubMed2001

Halipeptins A and B: two novel potent anti-inflammatory cyclic depsipeptides from the Vanuatu marine sponge Haliclona species.

Two new metabolites, named halipeptins A and B, have been isolated from the marine sponge Haliclona sp. Their structures were determined by extensive use of one- and two-dimensional NMR experiments, mass spectrometry, and UV and IR spectroscopy. Halipeptin A is a novel 17-membered cyclic depsipeptide, consisting of five residues including two alanines (with L stereochemistry) and three new residues that appear to be previously undescribed from natural sources: 1,2-oxazetidine-4-methyl-4-carboxylic acid, 3-hydroxy-2,2,4-trimethyl-7-methoxydecanoic acid (HTMMD), and N-methyl-delta-hydroxyisoleucine. The HTMMD residue is substituted with 3-hydroxy-2,2,4-trimethyl-7-hydroxydecanoic acid in halipeptin B. Halipeptin A was found to possess very potent anti-inflammatory activity in vivo, causing about 60% inhibition of edema in mice at the dose of 300 microg/kg (i.p.).

Animals↗
PubMed2001

Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues.

The hepatitis B virus (HBV) X protein (HBx) is a transcriptional transactivator that has been implicated in the development of HBV-related hepatocellular carcinoma. Mutations in the HBx open reading frame have been reported, but their general impact on the biological function of HBx remains unknown. To address this issue, we comparatively analyzed the structures and biological functions of HBx sequences isolated from sera and from tumor and nontumor tissues of patients with a HBV-related hepatocellular carcinoma. In addition to the HBx sequences derived from free HBV genomes, HBx from HBV integrants was also obtained from the tumor tissues by use of a HBx-Alu PCR-based approach. Sequence analysis showed that the HBx sequences derived from tumor tissues (6 of 7), particularly those isolated from HBV integrants (4 of 4), contained a deletion in the distal COOH-terminal region. Interestingly, most of the COOH-terminally truncated HBx sequences obtained from tumor tissues, in contrast to the full-length HBx isolated from the sera and nontumor tissues, lost their transcriptional activity and their inhibitory effects on cell proliferation and transformation. Importantly, although full-length HBx suppressed the focus formation induced by the cooperation of ras and myc oncogenes in primary rat embryo fibroblasts, COOH-terminally truncated HBx enhanced the transforming ability of ras and myc. Finally, by analyzing the artificial mutants, we were able to more precisely map the functional domains located at the COOH-terminal of HBx. Taken together, our results suggest a key role for the HBx COOH-terminal end in controlling cell proliferation, viability, and transformation. This study further supports the hypothesis that natural HBx mutants might be selected in tumor tissues and play a role in hepatocarcinogenesis by modifying the biological functions of HBx.

Amino Acid Sequence↗
PubMed2001

Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis.

Chronic hepatitis B virus (HBV) infection and the integration of its X gene (HBx) are closely associated with the development of hepatocellular carcinoma (HCC). The integrated HBx frequently is truncated or contains point mutations. Previous studies indicated that these HBx mutants have a diminished co-transactivational activity. We have compared the effects of wild-type (wt) HBx and its naturally occurring mutants derived from human HCCs on transcriptional co-transactivation, apoptosis and interactive effects with p53. We demonstrated that overexpression of mutant, but not wt HBx, is defective in transcriptional co-transactivation of the NF-kappaB-driven luciferase reporter. By using a microinjection technique, the HBx mutants were shown to have an attenuated pro-apoptotic activity. This deficiency may be attributed to multiple mutations in the co-transactivation domain of HBx, that leads to decreased stability of the translated product. However, wt or mutant HBx bind to p53 in vitro and retain their ability to block p53-mediated apoptosis in vivo, which has been implicated as its major tumor suppressor function. The abrogation of p53-mediated apoptosis by integrated HBx mutants may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to hepatocellular carcinogenesis.

Amino Acid Sequence↗
PubMed2001

Determination of flumethasone in calf urine and serum by liquid chromatography-tandem mass spectrometry.

Corticosteroids can be illegally administered to cattle as growth promoting agents to improve meat production. We developed a liquid chromatography-atmospheric pressure ionization mass spectrometry-mass spectrometry (LC-MS-MS) method able to identify and quantify flumethasone, one of the most potent fluorinated synthetic corticosteroid, in serum and urine from treated calves. The analyte was purified from urine (conjugated and free, following enzymatic hydrolysis) and from serum by C18 solid-phase and liquid-liquid extractions, then analyzed by LC-MS-MS monitoring the product ions of an abundant precursor (SRM in negative ionization mode). Results on flumethasone residues in biological fluids in three calves treated at different levels are presented. This method allowed the detection of flumethasone in bovine urine and serum at the 30-pg/ml level.

Animal Husbandry↗
PubMed2001

Cushing's disease due to plurihormonal adrenocorticotropic hormone and gonadotropin-producing pituitary adenoma.

A 67-year-old woman presented with clinical features of hypercortisolism in association with an invasive pituitary macroadenoma. Adrenocorticotropic hormone (ACTH)-dependent Cushing's disease was documented, and the resected tumor was chromophobic, weakly positive with periodic-Schiff reagent, and showed immunostaining for ACTH and beta-endorphin in a minority of adenoma cells. Both luteinizing hormone and alpha-subunit staining were also observed, but no follicle-stimulating hormone reactivity was seen. Ultrastructurally, the tumor showed typical features of a gonadotroph adenoma of female type. Immunoelectron microscopy showed that ACTH was not produced in corticotrophs, but in cells with the characteristic features of gonadotrophs. This represents the second report of a plurihormonal gonadotroph adenoma producing sufficient ACTH to result in pituitary-dependent Cushing's disease.

Adenoma↗
PubMed2001

Analysis of p53 mutation and expression in pleomorphic xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is a rare, superficially situated tumor that most frequently occurs in the temporal lobe of young adults and is often associated with seizures. It generally has a relatively favorable prognosis. Prior studies have shown that TP53 mutations may occur in up to 25% of PXAs, suggesting that PXA may have an etiology similar to diffuse astrocytoma rather than pilocytic astrocytoma. In the present study, we performed immunostaining for p53 protein and examined the mutation status of exons 5-8 of the p53 gene in 55 PXAs, 8 of which had undergone one or multiple recurrences. Of 55 primary PXAs, 35 (64%) showed staining in <1% of tumor cells, 15 (27%) in 1-10%, 4 (7%) in 11-50%, and only 1 (2%) in >50%. No significant increase in p53 protein expression was noted in recurrences, even when associated with increased histological anaplasia. We found a TP53 heterozygous mutation in exon 7 in 1 of 47 primary tumors that yielded useable DNA, and in its recurrence 3 years later. This tumor, a grade II PXA, did not show signs of anaplastic transformation at recurrence. Eleven additional recurrences from 7 patients, 5 of which showed signs of histological anaplasia, did not show TP53 mutations in exons 5-8. Based on our data, the p53 mutation appears to be an uncommon (2%) genetic event in PXA formation and does not appear to be involved in tumor progression. Consequently, our findings suggest that the genetic events that underlie PXA formation differ from those involved in diffuse astrocytoma.

Astrocytoma↗
PubMed2001

Dysidotronic acid, a new sesquiterpenoid, inhibits cytokine production and the expression of nitric oxide synthase.

In a previous study, we reported a new bioactive sesquiterpenoid, named dysidotronic acid, to be a potent, selective human synovial phospholipase A(2) inhibitor. Dysidotronic acid is a novel, non-complex manoalide analogue lacking the pyranofuranone ring. We now investigate the effect of this compound on cytokine, nitric oxide and prostanoid generation on the mouse macrophage cell line RAW 264.7, where it showed a dose-dependent inhibition with inhibitory concentration 50% values in the micromolar range. This effect was also confirmed in the mouse air pouch injected with zymosan. Dysidotronic acid inhibited the production of tumor necrosis factor alpha and interleukin-1 beta as well as the production of nitric oxide, prostaglandin E(2) and leukotriene B(4). Decreased nitric oxide generation was the consequence of inhibition of the expression of nitric oxide synthase, whereas PGE(2) and LTB(4) reduction was due to inhibition of arachidonic acid bioavailability through a direct inhibitory effect of dysodotronic acid on secretory phospholipase A(2).

Animals↗
PubMed2001

New sesquiterpene derivatives from the sponge Dysidea species with a selective inhibitor profile against human phospholipase A2 and other leukocyte functions.

Two new sesquiterpene cyclopentenones, dysidenones A and B (2, 3), and a new sesquiterpene aminoquinone, dysidine (4), all containing the same rearranged drimane skeleton, have been isolated from a Dysidea sp. sponge, along with bolinaquinone (1). The structures were established from 2D NMR data. Bolinaquinone (1), dysidine (4), and a 1:1 mixture of dysidenones A and B (2, 3) significantly inhibited human synovial phospholipase A2 (PLA2) at 10 microM. Compound 4, which shows an IC50 value of 2.0 microM, exerts a higher potency and selectivity toward this enzyme than the reference inhibitor manoalide. In addition, all of these compounds modulated at 10 microM other human leukocyte functions such as the degranulation process measured as elastase release and the superoxide production measured by chemiluminescence.

Animals↗
PubMed2001

Aggressive phenotypic and genotypic features in pediatric and NF2-associated meningiomas: a clinicopathologic study of 53 cases.

Pediatric and NF2-associated meningiomas are uncommon and poorly characterized in comparison to sporadic adult cases. In order to elucidate their molecular features, we analyzed MIB-1, progesterone receptor (PR), NF2, merlin, DAL-1, DAL-1 protein, and chromosomal arms 1p and 14q in 53 meningiomas from 40 pediatric/NF2 patients using immunohistochemistry and dual-color fluorescence in situ hybridization (FISH). Fourteen pediatric (42%) patients, including 5 previously undiagnosed patients, had NF2. The remaining 19 (58%) did not qualify. All 7 of the adult patients had NF2. Meningioma grading revealed 21 benign (40%), 26 atypical (49%), and 6 anaplastic (11%) examples. Other aggressive findings included high mitotic index (32%), high MIB-1 LI (37%), aggressive variant histology (e.g. papillary, clear cell) (25%), brain invasion (17%), recurrence (39%), and patient death (17%). FISH analysis demonstrated deletions of NF2 in 82%, DAL-1 in 82%, 1p in 60%, and 14q in 66%. NF2-associated meningiomas did not differ from sporadic pediatric tumors except for a higher frequency of merlin loss in the former (p = 0.020) and a higher frequency of brain invasion in the latter (p = 0.007). Thus, although pediatric and NF2-associated meningiomas share the common molecular alterations of their adult, sporadic counterparts, a higher fraction are genotypically and phenotypically aggressive. Given the high frequency of undiagnosed NF2 in the pediatric cases, a careful search for other features of this disease is warranted in any child presenting with a meningioma.

Adolescent↗